Vascular endothelial growth factor

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Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that
stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen
supply to tissues when blood circulation is inadequate.
VEGF's normal function is to create new blood vessels during embryonic development, new
blood vessels after injury, muscle following exercise, and new vessels (collateral circulation)
to bypass blocked vessels.
When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond
a limited size without an adequate blood supply; cancers that can express VEGF are able to
grow and metastasize. Overexpression of VEGF can cause vascular disease in the retina of
the eye and other parts of the body. Drugs such as bevacizumab can inhibit VEGF and control
or slow those diseases.
VEGF is a sub-family of growth factors, to be specific, the platelet-derived growth factor
family of cystine-knot growth factors. They are important signaling proteins involved in both
vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis
(the growth of blood vessels from pre-existing vasculature).

Contents
[hide]

1 Classification

2 Alternative classification

3 Mechanism

4 Production

5 Clinical significance

6 Anti-VEGF therapies
o 6.1 Pre-clinical

7 Ranibizumab vs. Bevacizumab for Treating Neovascular Age-related Macular

Degeneration

8 See also

9 References

10 External links

11 Further reading

[edit] Classification
The most important member is VEGF-A. Other members are Placenta growth factor (PlGF),
VEGF-B, VEGF-C and VEGF-D. The latter ones were discovered later than VEGF-A, and,
before their discovery, VEGF-A was called just VEGF.

Crystal structure of Vammin, a VEGF-F from a snake venom

A number of VEGF-related proteins have also been discovered encoded by viruses (VEGF-E)
and in the venom of some snakes (VEGF-F).

Type
VEGFA

Comparison
Function

Angiogenesis
o Migration of endothelial cells
o mitosis of endothelial cells
o Methane monooxygenase activity
o v3 activity

o creation of blood vessel lumen

o creates fenestrations

Chemotactic for macrophages and granulocytes

Vasodilation (indirectly by NO release)

VEGFEmbryonic angiogenesis
B
VEGFLymphangiogenesis
C
VEGFNeeded for the development of lymphatic vasculature surrounding lung bronchioles
D
Important for Vasculogenesis, Also needed for angiogenesis during ischemia,
PlGF
inflammation, wound healing, and cancer.
Activity of VEGF-A, as its name implies, has been studied mostly on cells of the vascular
endothelium, although it does have effects on a number of other cell types (e.g., stimulation
monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells). In vitro,
VEGF-A has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGFA is also a vasodilator and increases microvascular permeability and was originally referred
to as vascular permeability factor.

[edit] Alternative classification

Schematic representation of The different isoforms of human VEGF

The broad term 'VEGF' covers a number of proteins from two families, that result from
alternate splicing of mRNA from a single, 8-exon, VEGF gene. The two different families are
referred to according to their terminal exon (exon 8) splice site - the proximal splice site
(denoted VEGFxxx) or distal splice site (VEGFxxxb). In addition, alternate splicing of exon 6
and 7 alters their heparin-binding affinity, and amino acid number (in humans: VEGF121,
VEGF121b, VEGF145, VEGF165, VEGF165b, VEGF189, VEGF206; the rodent orthologs of these
proteins contain one fewer amino acid). These domains have important functional
consequences for the VEGF splice variants, as the terminal (exon 8) splice site determines

whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis)
or anti-angiogenic (distal splice site, expressed in normal tissues). In addition, inclusion or
exclusion of exons 6 and 7 mediate interactions with heparan sulfate proteoglycans (HSPGs)
and neuropilin co-receptors on the cell surface, enhancing their ability to bind and activate
the VEGF receptors (VEGFRs).

Types of VEGF and their VEGF receptors.[1]

[edit] Mechanism
All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase
receptors (the VEGFRs) on the cell surface, causing them to dimerize and become activated
through transphosphorylation, although to different sites, times and extents. The VEGF
receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single
transmembrane spanning region, and an intracellular portion containing a split tyrosinekinase domain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2
appears to mediate almost all of the known cellular responses to VEGF.[2] The function of
VEGFR-1 is less well-defined, although it is thought to modulate VEGFR-2 signaling.
Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF
from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in
the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor
(VEGFR-3), which mediates lymphangiogenesis.

[edit] Production
VEGFxxx production can be induced in cells that are not receiving enough oxygen. When a
cell is deficient in oxygen, it produces HIF, hypoxia-inducible factor, a transcription factor.
HIF stimulates the release of VEGFxxx, among other functions (including modulation of
erythropoeisis). Circulating VEGFxxx then binds to VEGF Receptors on endothelial cells,
triggering a Tyrosine Kinase Pathway leading to angiogenesis.
HIF1 alpha and HIF1 beta are constantly being produced but HIF1 alpha is highly O2 labile,
so, in aerobic conditions, it is degraded. When the cell becomes hypoxic, HIF1 alpha persists
and the HIF1alpha/beta complex stimulates VEGF release.

[edit] Clinical significance

VEGFxxx has been implicated with poor prognosis in breast cancer. Numerous studies show a
decreased overall survival and disease-free survival in those tumors overexpressing VEGF.
The overexpression of VEGFxxx may be an early step in the process of metastasis, a step that
is involved in the "angiogenic" switch. Although VEGFxxx has been correlated with poor
survival, its exact mechanism of action in the progression of tumors remains unclear.
VEGFxxx is also released in rheumatoid arthritis in response to TNF-, increasing endothelial
permeability and swelling and also stimulating angiogenesis (formation of capillaries).
VEGFxxx is also important in diabetic retinopathy (DR). The microcirculatory problems in the
retina of people with diabetes can cause retinal ischaemia, which results in the release of
VEGFxxx, and a switch in the balance of pro-angiogenic VEGFxxx isoforms over the normally
expressed VEGFxxxb isoforms. VEGFxxx may then cause the creation of new blood vessels in
the retina and elsewhere in the eye, heralding changes that may threaten the sight.
VEGFxxx plays a role in the disease pathology of the wet form age-related macular
degeneration (AMD), which is the leading cause of blindness for the elderly of the
industrialized world. The vascular pathology of AMD shares certain similarities with diabetic
retinopathy, although the cause of disease and the typical source of neovascularization
differes between the two diseases.
VEGF-D serum levels are significantly elevated in patients with angiosarcoma.[3]
Once released, VEGFxxx may elicit several responses. It may cause a cell to survive, move, or
further differentiate. Hence, VEGF is a potential target for the treatment of cancer. The first
anti-VEGF drug, a monoclonal antibody named bevacizumab, was approved in 2004.
Approximately 10-15% of patients benefit from bevacizumab therapy; however, biomarkers
for bevacizumab efficacy are not yet known.
Current studies show that VEGFs are not the only promoters of angiogenesis. In particular
FGF2 and HGF are potent angiogenic factors.
Patients suffering from pulmonary emphysema have been found to have decreased levels of
VEGF in the pulmonary arteries.
In the kidney, increased expression of VEGFxxx in glomeruli directly causes the glomerular
hypertrophy that is associated with proteinuria.[4]

[edit] Anti-VEGF therapies

Anti-VEGF therapies are important in the treatment of certain cancers and in age-related
macular degeneration. They can involve monoclonal antibodies such as bevacizumab
(Avastin), antibody derivatives such as ranibizumab (Lucentis), or orally-available small
molecules that inhibit the tyrosine kinases stimulated by VEGF: lapatinib (Tykerb), sunitinib
(Sutent), sorafenib (Nexavar), axitinib, and pazopanib. (Some of these therapies target VEGF
receptors rather than the VEGFs.)
Both antibody-based compounds are commercialized. The first three orally available
compounds are commercialized, as well. The latter two (axitinib and pazopanib) are in

clinical trials, the results of which were presented (June 7) at the American Society of
Clinical Oncology meeting.
Bergers and Hanahan concluded in 2008 that anti-VEGF drugs can show therapeutic efficacy
in mouse models of cancer and in an increasing number of human cancers. But, "the benefits
are at best transitory and are followed by a restoration of tumour growth and progression." [5]
AZ2171 (Cediranib), a multi-targeted tyrosine kinase inhibitor has been shown to have antiedema effects by reducing the permeability and aiding in vascular normalization.

[edit] Pre-clinical
VEGF is also inhibited by thiazolidinediones (used for diabetes mellitus type 2 and related
disease), and this effect on granulosa cells gives the potential of thiazolidinediones to be used
in ovarian hyperstimulation syndrome. [6]

[edit] Ranibizumab vs. Bevacizumab for Treating

Neovascular Age-related Macular Degeneration
Ranibizumab, a monoclonal antibody fragment (Fab) derived from bevacizumab, has been
developed by Genetech for intraocular use. In 2004, FDA approved the drug for oncologic
use to treat neovascular age-related macular degeneration (wet AMD). The drug has
undergone extensive clinical trials.
In the October 2006 issue of the New England Journal of Medicine (NEJM), Rosenfield, et
al. reported that monthly intravitreal injection of ranibizumab led to significant increase in the
level of mean visual acuity compared to that of sham injection. It was concluded from the
two year, phase III study that ranibizumab is very effective in the treatment of minimally
classic (MC) or occult wet AMD with low rates of ocular adverse effects. [7]
Another study published in the January 2009 issue of Ophthalmology provides the evidence
for the efficacy of ranibizumab. Brown, et al. reported that monthly intravitreal injection of
ranibizumab led to significant increase in the level of mean visual acuity compared to that of
photodynamic therapy with verteporfin. It was concluded from the two year, phase III study
that ranibizumab was superior to photodynamic therapy with verteporfin in the treatment of
predominantly classic (PC) Wet AMD with low rates of ocular adverse effects. [8]
Although the efficacy of ranibizumab is well supported by extensive clinical trials, the cost
effectiveness of the drug is questioned. Since the drug merely stabilizes patient conditions,
ranibizumab must be administered monthly. At a cost of $2,000.00 per injection, the cost to
treat wet AMD patients in the United States is greater than $10.00 billion per year. Due to
high cost, many ophthalmologists have turned to bevacizumab as the alternative intravitreal
agent in the treatment of wet AMD. The drug costs $15.00 to 50.00 in the United States.
In 2007, Raftery, et al. reported in the British Journal of Ophthalmology that, unless
ranibizumab is 2.5 times more effective the bevacizumab, ranibizumab is not cost effective. It
was concluded that the price of ranibizumab would have to be drastically reduced for the
drug to be cost effective.[9]

Off-label use of intravitreal bevacizumab has become a widespread treatment for neovascular
age-related macular degeneration.[10] Although the drug is not FDA approved for oncologic
uses, some studies suggest that bevacizumab is effective in increasing visual acuity with low
rates of ocular adverse effects. However, due to small sample size and lack of randomized
control trial, the result is not conclusive.
In October 2006, the National Eye Institute (NEI) of the National Institutes of Health (NIH)
announced that it would fund a comparative study trial of ranibizumab and bevacizumab to
assess the relative efficacy and ocular adversity in treating wet AMD. This study, called the
Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), will
enroll about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients
to different treatment groups.

[edit] See also

Proteases in angiogenesis

[edit] References
1.

^ cancerpublications.com.

2.

^ Holmes, Katherine; Roberts, Owain Ll; Thomas, Angharad M.; Cross,

Michael J. (2007). "Vascular endothelial growth factor receptor-2: Structure, function,
intracellular signalling and therapeutic inhibition". Cellular Signalling 19 (10): 2003
12. doi:10.1016/j.cellsig.2007.05.013. PMID 17658244.

3.

^ Amo, Y.; Masuzawa, M.; Hamada, Y.; Katsuoka, K. (2004). "Serum

concentrations of vascular endothelial growth factor-D in angiosarcoma patients".
British Journal of Dermatology 150 (1): 1601. doi:10.1111/j.13652133.2004.05751.x. PMID 14746640.

4.

^ Liu, E.; Morimoto, M.; Kitajima, S.; Koike, T.; Yu, Y.; Shiiki, H.; Nagata,
M.; Watanabe, T. et al. (2007). "Increased Expression of Vascular Endothelial Growth
Factor in Kidney Leads to Progressive Impairment of Glomerular Functions". Journal
of the American Society of Nephrology 18 (7): 2094104.
doi:10.1681/ASN.2006010075. PMID 17554151.

5.

^ Bergers G, Hanahan D (August 2008). "Modes of resistance to antiangiogenic therapy". Nat. Rev. Cancer 8 (8): 592603. doi:10.1038/nrc2442.
PMC 2874834. PMID 18650835.
http://www.nature.com/nrc/journal/v8/n8/abs/nrc2442.html.

6.

^ Shah DK, Menon KM, Cabrera LM, Vahratian A, Kavoussi SK, Lebovic DI
(April 2010). "Thiazolidinediones decrease vascular endothelial growth factor
(VEGF) production by human luteinized granulosa cells in vitro". Fertil. Steril. 93
(6): 20427. doi:10.1016/j.fertnstert.2009.02.059. PMC 2847675. PMID 19342033.

7.

^ Brown, David M.; Michels, Mark; Kaiser, Peter K.; Heier, Jeffrey S.; Sy,
Judy P.; Ianchulev, Tsontcho; Anchor Study, Group (2009). "Ranibizumab versus

Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular

Degeneration: Two-Year Results of the ANCHOR Study". Ophthalmology 116 (1):
5765. doi:10.1016/j.ophtha.2008.10.018. PMID 19118696.
8.

^ Rosenfeld, Philip J.; Brown, David M.; Heier, Jeffrey S.; Boyer, David S.;
Kaiser, Peter K.; Chung, Carol Y.; Kim, Robert Y.; Marina Study, Group (2006).
"Ranibizumab for Neovascular Age-Related Macular Degeneration". New England
Journal of Medicine 355 (14): 141931. doi:10.1056/NEJMoa054481.
PMID 17021318.

9.

^ Raftery, J.; Clegg, A.; Jones, J.; Tan, S. C.; Lotery, A. (2007). "Ranibizumab
(Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness". British
Journal of Ophthalmology 91 (9): 12446. doi:10.1136/bjo.2007.116616.
PMC 1954941. PMID 17431015.

10.

^ http://patentdocs.typepad.com/patent_docs/2007/10/genentech-acts-.html

[edit] External links

MeSH Vascular+Endothelial+Growth+Factors

Proteopedia Vascular_Endothelial_Growth_Factor - the Vascular Endothelial Growth

Factor Structure in Interactive 3D

[edit] Further reading

Bengoetxea H, Argandoa EG, Lafuente JV (2008). "Effects of visual experience on

vascular endothelial growth factor expression during the postnatal development of the
rat visual cortex.". Cerebral Cortex. 18 (7): 163039. doi:10.1093/cercor/bhm190.
PMC 2430152. PMID 17986606.

Ferrara N, Gerber HP (2002). "The role of vascular endothelial growth factor in

angiogenesis". Acta Haematol. 106 (4): 14856. doi:10.1159/000046610.
PMID 11815711.

Orpana A, Salven P (2003). "Angiogenic and lymphangiogenic molecules in

hematological malignancies". Leuk. Lymphoma 43 (2): 21924.
doi:10.1080/10428190290005964. PMID 11999550.

Afuwape AO, Kiriakidis S, Paleolog EM (2003). "The role of the angiogenic

molecule VEGF in the pathogenesis of rheumatoid arthritis". Histol. Histopathol. 17
(3): 96172. PMID 12168808.

de Bont ES, Neefjes VM, Rosati S, et al. (2003). "New vessel formation and aberrant
VEGF/VEGFR signaling in acute leukemia: does it matter?". Leuk. Lymphoma 43
(10): 19019. doi:10.1080/1042819021000015844. PMID 12481883.

Ria R, Roccaro AM, Merchionne F, et al. (2003). "Vascular endothelial growth factor
and its receptors in multiple myeloma". Leukemia 17 (10): 19616.
doi:10.1038/sj.leu.2403076. PMID 14513045.

Caldwell RB, Bartoli M, Behzadian MA, et al. (2004). "Vascular endothelial growth
factor and diabetic retinopathy: pathophysiological mechanisms and treatment
perspectives". Diabetes Metab. Res. Rev. 19 (6): 44255. doi:10.1002/dmrr.415.
PMID 14648803.

Patan S (2004). "Vasculogenesis and angiogenesis". Cancer Treat. Res. 117: 332.
PMID 15015550.

Machein MR, Plate KH (2004). "Role of VEGF in developmental angiogenesis and in

tumor angiogenesis in the brain". Cancer Treat. Res. 117: 191218. PMID 15015562.

Eremina V, Quaggin SE (2004). "The role of VEGF-A in glomerular development and

function". Curr. Opin. Nephrol. Hypertens. 13 (1): 915. doi:10.1097/00041552200401000-00002. PMID 15090854.

Storkebaum E, Lambrechts D, Carmeliet P (2004). "VEGF: once regarded as a

specific angiogenic factor, now implicated in neuroprotection". Bioessays 26 (9):
94354. doi:10.1002/bies.20092. PMID 15351965.

Ribatti D (2005). "The crucial role of vascular permeability factor/vascular

endothelial growth factor in angiogenesis: a historical review". Br. J. Haematol. 128
(3): 3039. doi:10.1111/j.1365-2141.2004.05291.x. PMID 15667531.

Loureiro RM, D'Amore PA (2005). "Transcriptional regulation of vascular endothelial

growth factor in cancer". Cytokine Growth Factor Rev. 16 (1): 7789.
doi:10.1016/j.cytogfr.2005.01.005. PMID 15733833.

Rini BI (2005). "VEGF-targeted therapy in metastatic renal cell carcinoma".

Oncologist 10 (3): 1917. doi:10.1634/theoncologist.10-3-191. PMID 15793222.

Herbst RS, Onn A, Sandler A (2005). "Angiogenesis and lung cancer: prognostic and
therapeutic implications". J. Clin. Oncol. 23 (14): 324356.
doi:10.1200/JCO.2005.18.853. PMID 15886312.

Pufe T, Kurz B, Petersen W, et al. (2006). "The influence of biomechanical

parameters on the expression of VEGF and endostatin in the bone and joint system".
Ann. Anat. 187 (5-6): 46172. doi:10.1016/j.aanat.2005.06.008. PMID 16320826.

Tong JP, Yao YF (2006). "Contribution of VEGF and PEDF to choroidal

angiogenesis: a need for balanced expressions". Clin. Biochem. 39 (3): 26776.
doi:10.1016/j.clinbiochem.2005.11.013. PMID 16409998.

Lambrechts D, Carmeliet P (2007). "VEGF at the neurovascular interface: therapeutic

implications for motor neuron disease". Biochim. Biophys. Acta 1762 (11-12): 1109
21. doi:10.1016/j.bbadis.2006.04.005. PMID 16784838.

Matsumoto T, Mugishima H (2006). "Signal transduction via vascular endothelial

growth factor (VEGF) receptors and their roles in atherogenesis". J. Atheroscler.
Thromb. 13 (3): 1305. PMID 16835467.

Bogaert E, Van Damme P, Van Den Bosch L, Robberecht W (2006). "Vascular

endothelial growth factor in amyotrophic lateral sclerosis and other neurodegenerative
diseases". Muscle Nerve 34 (4): 391405. doi:10.1002/mus.20609. PMID 16856151.

Mercurio AM, Lipscomb EA, Bachelder RE (2006). "Non-angiogenic functions of

VEGF in breast cancer". Journal of mammary gland biology and neoplasia 10 (4):
28390. doi:10.1007/s10911-006-9001-9. PMID 16924371.

Makinde T, Murphy RF, Agrawal DK (2007). "Immunomodulatory role of vascular

endothelial growth factor and angiopoietin-1 in airway remodeling". Curr. Mol. Med.
6 (8): 83141. doi:10.2174/156652406779010795. PMID 17168735.

Rini BI, Rathmell WK (2007). "Biological aspects and binding strategies of vascular
endothelial growth factor in renal cell carcinoma". Clin. Cancer Res. 13 (2 Pt 2):
741s-746s. doi:10.1158/1078-0432.CCR-06-2110. PMID 17255303.

Rodgers LS, Lalani S, Hardy KM, Xiang X, Broka D, Antin PB, Camenisch TD.
(2006). "Depolymerized hyaluronan induces vascular endothelial growth factor, a
negative regulator of developmental epithelial-to-mesenchymal transformation.". Circ
Res. 99 (6): 5839. doi:10.1161/01.RES.0000242561.95978.43. PMID 16931798.

[show]v d eProteins: angiogenesis

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Retrieved from "http://en.wikipedia.org/wiki/Vascular_endothelial_growth_factor"

Categories: Angiology | Growth factors

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Proteases in angiogenesis
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a
highly complex process involving extensive interplay between cells, soluble factors, and the
extracellular matrix (ECM). Angiogenesis is critical during normal physiological
development, but it also occurs in adults during inflammation, wound healing, ischemia, and
in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth.[1][2]
Proteolysis has been indicated as one of the first and most sustained activities involved in the
formation of new blood vessels. Numerous proteases including matrix metalloproteases
(MMPs), a disintegrin and metalloprotease domain (ADAM), a disintegrin and
metalloprotease domain with throbospondin motifs (ADAMTS), and cysteine and serine
proteases are involved in angiogenesis. This article focuses on the important and diverse roles
that these proteases play in the regulation of angiogenesis.

Contents
[hide]

1 MMPs

2 ADAM/ADAMTS

3 Other proteolytic enzymes

4 Ectodomain shedding

5 Proteolytic degradation of the extracellular matrix (ECM)

6 Proteolytic fragments as regulators of angiogenesis

7 Proteolytic activation of growth factors

8 Proteases as inhibitors of angiogenesis

9 Proteolysis and cell migration

10 Uncontrolled proteolysis of the ECM

11 Proteases involved in the recruitment of bone marrow derived cells during

angiogenesis

12 Maturation of newly formed blood vessels via proteases

13 Perspective

14 References

[edit] MMPs
MMPs are a large multigene family of zinc-dependent endopeptidases. The collective MMP
family is capable of degrading all known ECM macromolecules. MMP activity is regulated at
the level of transcription as well as by endogenous inhibitors known as tissue inhibitors of
metalloproteases (TIMPs). The role of matrix metalloproteases and TIMPs in several
pathological conditions including angiogenesis, tumor growth, and metastasis has been
investigated and very well described.
Matrix metalloproteases contain five conserved domain structures:
1. Signal peptide domain, which directs the enzyme into the rough endoplasmic
reticulum during synthesis
2. Propeptide domain, which is cleaved during the activity of the enzyme
3. Catalytic domain, which contains the conserved Zn2+ binding region and facilitates
enzyme activity

4. Hemopexin domain, which provides the substrate specificity

5. Small hinge region, which allows the hemopexin domain to bring the substrate to the
active core of the catalytic domain
There is also a subfamily of the matrix metalloproteases, the membrane-type MMPs (MTMMPs) which contain an additional transmembrane domain and a short cytoplasmic domain.
After activation of MMPs by removal of the propeptide domain, their activity is regulated by
TIMPs. TIMPs specifically and reversibly inhibit the activity of MMPs. So far there have
been identified four members of the family, TIMP14. All TIMPs contain twelve conserved
cystein residues, which form six disulfide bonds. The C-terminal domains of TIMPs are
highly variable and confer their specificity towards preferred MMP targets.[3][4]

[edit] ADAM/ADAMTS

ADAM17
ADAMs comprise a family of integral membrane as well as secreted glycoproteins which are
related to snake venom metalloproteases and MMPs. Like MMPs, ADAMs are composed of
multiple conserved domains. They contain propeptide, metalloprotease, disintegrin-like,
cystein-rich, and epidermal growth factor like domains. Membrane anchored ADAMs contain
a transmembrane and cytoplasmic domain. The domains contained within the ADAMs family
have been characterized, uncovering their functional and structural roles.[5] ADAMs contain a
consensus sequence which has three histidine residues that bind to the catalytically essential
zinc ion. The propeptide is removed through cleavage by a furin type protease yielding the
active enzyme. The propeptide of most MMPs is cleavable by proteases such as trypsin,
plasmin, chymotrypsin and other MMPs.[6] ADAMs participate in a wide variety of cell
surface remodeling processes, including ectodomain shedding, regulation of growth factor
availability and mediating cell-matrix interactions. ADAM17 and ADAM15 have recently
been identified in endothelial cells (EC).[7]
ADAMTS are a subfamily of ADAM related metalloproteases that contain at least one
thrombospondin type I sequence repeat motif (TSR). They are secreted proteins; and the TSR
facilitates their localization to the ECM placing it in close proximity to their substrates.
Functionally, ADAMTS can be divided into three groups: procollagen aminopepidase,
aggrecanase, and ADAMTS13 which cleaves von Willebrand factor. Unlike with MMPs,
TIMPs are more selective in their ability to inhibit ADAMs and ADAMTSs. TIMP3 is able to

inhibit ADAM17 and 12 as well as ADAMTS4 and 5. ADAM8 and ADAM9 are not
susceptible to inhibition by TIMPs.

[edit] Other proteolytic enzymes

Many additional classes of enzymes have been identified that facilitate angiogenesis. They
include serine, aspartic, and cysteine-type proteases. A highly characterized example of the
serine protease family is the plasminogen activator-plasmin system, which has been show to
be involved in vascular remodeling. Tissue plasminogen activator (tPA), and urokinase
plasminogen activator (urokinase, uPA) are serine proteases which cleave and activate
plasminogen. The activated form of plasminogen, plasmin, is a wide ranging protease capable
of acting on various ECM components including fibrin, collagens, laminin, fibronectin, and
proteoglycans.[8] Additionally, plasmin also is able to activate various other MMPs.
In humans, the group of cathepsin cysteine proteases or cysteine cathepsins comprises 11
family members, cathepsins B, C, F, H, L1, L2, K, O, S, W, and X/Z.[9] Cysteine cathepsins
are synthesized as inactive zymogens and activated by proteolytic removal of their
propeptide. These enzymes are primarily localized in lysosomes and function in terminal
protein degradation and processing. Cathepsins also can be secreted by cells, associate with
the cell surface, and degrade the ECM. A study of all 11 members of the cathepsin family
highlights their importance in tumorigenesis and tumor associated angiogenesis.[10]
Examination of cathepsin activity by using chemical probes and in vivo imaging techniques
demonstrated an increase in cathepsin activity in the angiogenic blood vessels and invasive
fronts of carcinoma in the RIP-Tag2 transgenic mouse model of pancreatic islet tumor
genesis.
Aminopeptidases function as exopeptidases which remove amino acids from the aminoterminus of proteins. Aminopeptidase N (CD13/APN) is highly expressed on the endothelium
of growing vessels.[11] Inhibitors of CD13/APN dramatically impair tumor growth.

[edit] Ectodomain shedding

Diagram of an ectodomain shedding ADAM metalloprotease.

It has become clear in the past years that ectodomain shedding is an initial step for the
activation of specific receptors such as Notch, ErbB-4 and the angiopoietin receptor Tie-1.
Notch-1 signaling is essential for endothelial differentiation, and tumor angiogenesis, while
the angiopoietin receptor Tie-1 facilitates embryonic blood vessel formation.[12][13] Upon
binding of their ligands, Notch-1 and Tie-1 undergo proteolytic cleavage of the ectodomains

by ADAM17 and ADAM10. This cleavage frees the cytoplasmic fragment for cellular
signaling, in the case of Notch-1, it transfers to the nucleus.
Many cytokines and growth factors are synthesized as membrane bound proforms which
undergo proteolytic shedding for activation. The ephrins EPH receptor A2 and A3 are shed by
ADAM10 creating cleaved soluble Eph receptors, which inhibit tumor angiogenesis in mice.
[14]
Additional examples are the proteolytic shedding of soluble E-selectin,[15] shedding of
urokinase receptor (uPAR) by MMP-12 creating soluble uPAR which has chemotactic
properties for leukocytes and progenitor cells, and the shedding of interleukin-6 receptors by
ADAM10 and ADAM17 which facilitates interleukin-6 signaling in endothelial cells.[16]
Semaphorin 4D is cleaved from its membrane bound form by MT1-MMP (MMP-14) in
tumor cells; it then interacts with plexin B1 on endothelial cells promoting pro-angiogenic
chemotaxis.[17] Shedding of a membrane anchored cytokine or growth factor by ADAM
proteinases may be relevant for various signal transduction events. Alternatively, shedding
may be required for the ligand to diffuse to distant receptors. Shedding may be required for
the down regulation of signals by removing signaling ligands, or cleavage and release of
receptors. Release of the receptor may also generate soluble receptors which act as decoys by
sequestering ligands. These findings indicate that ectodomain shedding is a ubiquitous
process facilitating a wide variety of cellular events involved in angiogenesis. Because potent
biological modifiers are generated, it is likely controlled by highly regulated mechanism.
Along with ADAMs and MT-MMPs, membrane bound serine proteases also may play a role
in ectodomain shedding.

[edit] Proteolytic degradation of the extracellular matrix

(ECM)

Illustration depicting extracellular matrix in relation to epithelium, endothelium and

connective tissue.
The formation of capillaries from pre-existing blood vessels requires the remodeling of both
the peicapillary membrane of the parent venule, as well as the local and distal ECM. At the
onset of angiogenesis endothelial cells (EC) must remodel three different barriers in order to
migrate and invade the target tissue. First is the basement membrane between the
endothelium and vascular smooth muscle cells or pericytes, followed by the fibrin gel formed
from fibrinogen that is leaked from the vasculature, and finally the extracellular matrix in the
target tissue. The vascular basement membrane is composed of type IV collagen, type XV
collagen, type XVIII collagen, laminins, entactin, heparan sulfate proteoglycans, perlecan,
and osteonectin. All of these components of the basement membrane are substrates for MMP2, 3, 7, and 9, among others. Inhibitors of MMP activity have spotlighted the importance of
these proteins in controlling angiogenesis. Recently, it has been discovered that small

interfering RNA (siRNA) mediated target RNA degradation of urokinase receptor and MMP9 inhibits the formation of capillary like structures in both in vitro and in vivo models of
angiogenesis.[18] After working their way through the basement membrane, EC must invade
through a dense fibrin gel which is polymerized from fibrinogen derived from the vascular
bed.[19] Plasmin, an effective fibrinolysin produced by tPA or uPA, was thought to be essential
in this process, but plasminogen deficient mice do not display major defects of
neovascularization in fibrin rich tissues.[20] These findings highlight the diverse amount of
proteolytic enzymes ECs use to remodel the ECM. For example, MMP-3, 7, 8, 12 and 13 can
cleave fibrinogen.[21]
MMP activity is one of the earliest and most sustained processes that take place during
angiogenesis. By studying the transition from an avascular to a vascular tumor Fang et al.
were able to identify the key role of MMP-2 in angiogenesis. MMP-2 expression and activity
was increased in angiogenic tumors as compared with avascular tumors, and the addition of
antisense oligonucleotides targeting MMP-2 inhibits the initiation of angiogenesis
maintaining the avascular phenotype. This data along with other reports suggest that MMP
activity is necessary to initiate the earliest stages of angiogenesis and tumor development.
The creation of MMP deficient mice has provided important insight into the role of MMPs in
the regulation of angiogenesis. For example, MMP-2 knockout mice develop normally but
display significant inhibition of corneal angiogenesis.[22]

[edit] Proteolytic fragments as regulators of angiogenesis

Numerous proteolytic fragments or domains of ECM proteins have been reported to exert
positive or negative activity on angiogenesis. Native proteins which contain such domains
with regulatory activity are normally inactive, most likely because they are cryptic segments
hidden in the native protein structure. Angiostatin is a 38 kDa plasminogen fragment with
angiogenesis inhibitor activity. Angiostatin fragments contain kringle domains which exert
their inhibitory activity at several different levels; they inhibit endothelial cell migration and
proliferation, increase apoptosis, and modulate the activity of focal adhesion kinase (FAK).
Endostatin is a 20 kDa fragment of collagen XVIII. The major role of endostatin is in its
ability to potently inhibit endothelial cell migration and induce apoptosis.[23] These effects are
mediated by interacting and interfering with various angiogenic related proteins such as
integrins and serine/threonine-specific protein kinases. Numerous studies have demonstrated
that tropoelastin, the soluble precursor of elastin, or proteolytic elastin fragments have diverse
biological properties. Nackman et al. demonstrated that elastase generated elastin fragments
mediate several characteristic features of aneurismal disease which correlated to
angiogenesis. Osteonectin is a metal binding glycoprotein produced by many cell types
including ECs. Lastly, endorepellin is a recently described inhibitor of angiogenesis derived
from the carboxy terminus of perlecan.[24] Nanomolar concentrations of endorepellin inhibits
EC migration and angiogenesis in different in vitro and in vivo models by blocking EC
adhesion to various substrate such as fibronectin and type I collagen.
Endogenous inhibitors or activators generated by proteolytic degradation of larger proteins
mostly from the ECM have proven to contribute to the regulation of tumor growth and
angiogenesis. This article mentions only a small fraction of the known proteolytic fragments
which alter EC behavior and function during angiogenesis. This abundance has garnered
increased attention because of their potential for anti-angiogenic and anti-cancer therapies.

[edit] Proteolytic activation of growth factors

Proteases not only modulate cell-matrix interactions but also can control the onset and
progression of angiogenesis by activating angiogenic growth factors and cytokines.
Hepatocyte growth factor (HGF), an angiogenesis promoting growth factor, is activated by
HGF activation factor, a serine protease related to plasminogen.[25] Several growth factors
such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)
are trapped in the ECM by various proteoglycans. The proteolytic degradation of these
proteoglycans liberates the growth factors allowing them to reach their receptors and
influence cellular behavior. Growth factors that indirectly affect angiogenesis are also targets
of proteolytic activation. For example, plasminogen activators drive the activation of latent
transforming growth factor beta (TGF-) from bone ECM and thus modulate angiogenesis in
bone.[26]
Proteases not only have the ability change the availability of growth factors, but can also
modify their properties. This ability was shown for VEGF165 that is cleaved by MMP-3 or
MMP-9 to a smaller molecule with properties similar to VEGF121.[27] These two isoforms of
VEGF have very different properties. VEGF165 induces a regular vessel pattern during tumor
neovascularization. VEGF121 and the truncated VEGF165, in contrast, cause irregular patterns
of neovascularization, most likely due to their inability to bind heparan sulfates, wherefore
they do not provide any spatial information that is buried in the ECM. Another important
factor in angiogenesis, stromal cell-derived factor-1 (SDF-1), is also modified by the
aminodipeptidase dipeptidyl peptidase-4 (DPP4). Cleavage of SDF-1 reduces it heparan
sulfate affinity and interactions with its receptor CXCR4 are reduced.[28] The ADAM family
of proteases is receiving increased attention for their ability to alter the balance between proand anti-angiogenic factors. ADAM17 is able to release active tumor necrosis factor-alpha
(TNF) and heparin-binding EGF-like growth factor (HB-EGF) from their membrane bound
precursors which can indirectly affect angiogenesis.[29]

[edit] Proteases as inhibitors of angiogenesis

Proteases not only facilitate angiogenesis, but they also have the ability to put the brakes on
the process. One example of this is the processing of angiogenesis inhibitors by MMPs. As
previously described, MMPs have been shown to cleave plasminogen and collagen XVIII
into the endogenous angiogenesis inhibitors angiostatin and endostatin. MMP-2 itself
possesses anti-angiogenic properties that are independent of its catalytic domain. Interactions
between integrin v3 and MMP-2 on the EC cell surface may be necessary for MMP-2
activity during angiogenesis. The hemopexin like domain in the carboxy terminus of MMP-2
is able to block this interaction of active MMP-2 and integrin v3 on the EC surface which
lead to inhibition of MMP-2 activity.[30]
During angiogenesis ADAM15 is preferentially expressed on EC. ADAM15 is able to
interact with integrins v3 and 51 through its disintegrin domain via an RGD (arginineglycine-aspartic acid) motif. Most disintegrins contain this conserved RGD motif, but
ADAM15 is the only member of the ADAM family to contain this motif. A recombinant
disintegrin domain of human ADAM15 inhibits a variety of EC functions in vitro including
proliferation, adhesion, migration, and capillary formation.[31] Overexpression of ADAM15
disintegrin domain resulted in inhibition of angiogenesis, tumor growth, and metastasis. On
the other hand it has not been shown whether full length ADAM15 plays an inhibitory role in

vivo. ADAMTS1 and ADAMTS8 inhibit angiogenesis in vitro in two functional angiogenesis
assays. Both enzymes inhibit bFGF induced vascularization in the corneal pocket assay and
inhibit VEGF induced angiogenesis in the chorioallantoic membrane assay.[32] All together,
these data indicate that proteases can function as both positive and negative regulators of
angiogenesis.

[edit] Proteolysis and cell migration

Angiogenesis requires the migration and invasive growth of cells. This is facilitated by a
balanced interplay between detachment and formation of cell adhesions which enable the cell
to crawl forward through the ECM.[33] The cell uses limited proteolytic activity at sites of
individual focal adhesions via the formation of multiprotein complexes. Multiprotein
complexes are localized in lipid rafts on the cell surface, where membrane bound proteases
are often incorporated. For example, leukocytes complex urokinase (uPA), urokinase receptor
(uPAR), and integrins which participate in cell adhesion and invasion.[34] In these complexes,
uPAR acts as an organizing center forming noncovalent complexes with integrins, LRP-like
proteins, and urokinase. Similar complexes also are found on ECs.

[edit] Uncontrolled proteolysis of the ECM

The proteolytic activities that take place during angiogenesis require precise spatial and
temporal regulation. If not for this control excessive proteolysis could lead to damage of the
tissue and the loss of anchorage points for migrating cells. This is illustrated by mice which
are deficient for plasminogen activator inhibitor-1 (PAI-1).[35][36] PAI-1 inhibits plasminogen
activators and thus plasmin activation; therefore it could be assumed that PAI-1 deficiency
would increase angiogenesis and tumor growth. Unexpectedly, when PAI-1 deficient mice
were challenged with cancer cells on a collagenous matrix, angiogenesis and vascular
stabilization was inhibited, hampering tumor growth. This finding was credited to the
protective properties PAI-1 imparts against excessive degradation of the surrounding ECM by
plasmin. Without this protection the footholds used by endothelial cells to migrate and form
capillary structures are destroyed. Uncontrolled proteolysis also is attributed to the disruption
of vascular development and premature deaths in murine embryos deficient of the inhibitor
reversion-inducing-cysteine-rich protein with kazal motifs (RECK). This is most likely due to
uncontrolled MMP activity, because a partial rescue was obtained by simultaneously
knocking out RECK and MMP-2.[37]

[edit] Proteases involved in the recruitment of bone

marrow derived cells during angiogenesis
Leukocytes and endothelial progenitor cells (EPCs) contribute to the initiation and guidance
of new blood vessels.[38] Monocytes produce a variety of pro-angiogenic factors. There is also
a population of CD34 positive cells that can express endothelial associated proteins, such as
VE-cadherin and kinase insert domain receptor (KDR, VEGF receptor 2) which aid in
influencing the progression of angiogenesis.[39] The absence or dysfunction of these cells is
implicated in impaired vascularization in cardiac and diabetes patients.[40] MMP-9 plays a key
role in mobilizing EPCs from the bone marrow. Heissig et al. have proposed a mechanism for
how MMP-9 facilitates the availability of EPCs for angiogenesis. First, circulating VEGF
induces MMP-9 expression in the bone marrow, MMP-9 then is able to cleave and release c-

kit ligand. Activated c-kit is then able to recruit hematopoietic, endothelial and mast cell
progenitor cells, these cells are then accumulated in the angiogenic area and produce large
amounts of VEGF tipping the scales in favor of angiogenesis.[41]
MMP-9 is not the only protease shown to be involved in EPC enhanced angiogenesis.
Cathepsin L is active at neutral pH by associating with a p41 splice variant of the MHC class
II-associated invariant chain which is strongly expressed in EPCs.[42] This ability to stay
active at neutral pH may facilitate EPC invasion, remodeling of matrix collagens and gelatin,
and neovascularization. Knock out of cathepsin L in mice exhibited impaired blood flow
restoration in ischemic limbs, indicating impaired neovascularization. Neovascularization
also is impaired in mice treated with bone marrow derived cells deficient of cathepsin L as
compared with wild type cells. The target by which cathepsin L stimulates angiogenesis is not
yet identified.

[edit] Maturation of newly formed blood vessels via

proteases

MT1-MMP (MMP-14)
It has been well established that smooth muscle-like pericytes play an important role in
stabilizing newly formed blood vessels. Pericytes present in the stroma of tumors of breast
cancer patients express MMP-9.[43] Animal models deficient of MMP-9 display disturbed
recruitment of pericytes.[44] The inability to recruit pericytes severely affects the stability of
vessels and the degree of vascularization of neuroblastomas. Aminopeptidase A also may be
involved in pericyte recruitment due to its increased expression by activated pericytes in
various pathological conditions associated with angiogenesis.[45] The mechanism by which
this protease facilitates vessel maturation has not yet been determined. Angiogenesis requires
a fine balance between proteolytic activity and proteinase inhibition. Pericytes secrete TIMP3 which inhibits MT1-MMP dependent MMP-2 activation on endothelial cell, thus
facilitating stabilization of newly formed microvessels. Co-cultures consisting of pericytes
and endothelial cells induce the expression of TIMP-3 by pericytes, while endothelial cells
produce TIMP-2.[46] Together, these inhibitors stabilize the vasculature by inhibiting a variety
of MMPs, ADAMs, and VEGF receptor 2.
Immature vessels remain dependent on continuous exposure the angiogenic growth factors
without pericyte coverage.[47] As the reservoir of growth factors is removed the endothelial

cells do not survive, and undergo caspases induced apoptosis, while other proteases
participate in the degradation and removal of the remaining cell debris.

[edit] Perspective
Proteases play numerous roles in angiogenesis, both in development and especially in
pathological conditions. Because they are important regulators of tissue degradation and cell
migration, it is expected that their inhibition would be beneficial for inhibiting tumor growth
and vascularization. Promising results have been observed in animal studies, but clinical trials
have failed to demonstrate similar results and are often accompanied by unacceptable side
effects.[48] This has influenced continued research which has identified new families of
proteases, such as ADAM, ADAMTS, and MT-MMPs. Perhaps more significantly, a new
paradigm has emerged for proteases being essential for modulating growth factors and
cytokines, generating biologically active fragments from the matrix, facilitating recruitment
of bone marrow derived cells, and stabilization of mature blood vessels. Better understanding
of the various activities of proteases and their inhibitors will aid in more tailor made
treatments for numerous disorders.

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doi:10.1083/jcb.200603176. PMC 2064509. PMID 17030988.

47.

^ Bergers, G; Song, S; Meyer-Morse, N; Bergsland, E; Hanahan, D (2003).

"Benefits of targeting both pericytes and endothelial cells in the tumor vasculature
with kinase inhibitors". J Clin Invest. 111 (9): 12871295. doi:10.1172/JCI17929.
PMC 154450. PMID 12727920.

48.

^ Coussens, L; Fingleton, B; Matrisian, LM (2002). "Matrix metalloproteinase

inhibitors and cancer: trials and tribulations". Science 295 (5564): 23872392.
doi:10.1126/science.1067100. PMID 11923519.
[show]v d eProteins: angiogenesis

M: anat(a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell noco/syva/cong/lyvd/tu
proc,
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[show]v d eHydrolase: proteases (EC 3.4)
3.4.11

Aminopeptidase (Alanine, Arginyl, Aspartyl, Cystinyl, Leucyl, Glutamyl,

Methionyl (1, 2), O)

3.4.13

Dipeptidase (1, 2, 3)

3.4.14

Dipeptidyl peptidase (Cathepsin C, Dipeptidyl peptidase-4) Tripeptidyl

peptidase (Tripeptidyl peptidase I, Tripeptidyl peptidase II)

3.4.15

Angiotensin-converting enzyme

3.4.16

Serine type carboxypeptidases: Cathepsin A DD-transpeptidase

3.4.17

Metallocarboxypeptidases: Carboxypeptidase (A, A2, B, C, E, Glutamate

II)

Other/ungroupe
Metalloexopeptidase
d

[show]v d eProteases: metalloendopeptidases (EC 3.4.24)

Retrieved from "http://en.wikipedia.org/wiki/Proteases_in_angiogenesis"

Categories: Angiology | Posttranslational modification | Peptidase
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Proteases in angiogenesis
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a
highly complex process involving extensive interplay between cells, soluble factors, and the
extracellular matrix (ECM). Angiogenesis is critical during normal physiological
development, but it also occurs in adults during inflammation, wound healing, ischemia, and
in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth.[1][2]
Proteolysis has been indicated as one of the first and most sustained activities involved in the
formation of new blood vessels. Numerous proteases including matrix metalloproteases
(MMPs), a disintegrin and metalloprotease domain (ADAM), a disintegrin and
metalloprotease domain with throbospondin motifs (ADAMTS), and cysteine and serine
proteases are involved in angiogenesis. This article focuses on the important and diverse roles
that these proteases play in the regulation of angiogenesis.

Contents

[hide]

1 MMPs

2 ADAM/ADAMTS

3 Other proteolytic enzymes

4 Ectodomain shedding

5 Proteolytic degradation of the extracellular matrix (ECM)

6 Proteolytic fragments as regulators of angiogenesis

7 Proteolytic activation of growth factors

8 Proteases as inhibitors of angiogenesis

9 Proteolysis and cell migration

10 Uncontrolled proteolysis of the ECM

11 Proteases involved in the recruitment of bone marrow derived cells during

angiogenesis

12 Maturation of newly formed blood vessels via proteases

13 Perspective

14 References

[edit] MMPs
MMPs are a large multigene family of zinc-dependent endopeptidases. The collective MMP
family is capable of degrading all known ECM macromolecules. MMP activity is regulated at
the level of transcription as well as by endogenous inhibitors known as tissue inhibitors of
metalloproteases (TIMPs). The role of matrix metalloproteases and TIMPs in several
pathological conditions including angiogenesis, tumor growth, and metastasis has been
investigated and very well described.
Matrix metalloproteases contain five conserved domain structures:
1. Signal peptide domain, which directs the enzyme into the rough endoplasmic
reticulum during synthesis
2. Propeptide domain, which is cleaved during the activity of the enzyme

3. Catalytic domain, which contains the conserved Zn2+ binding region and facilitates
enzyme activity
4. Hemopexin domain, which provides the substrate specificity
5. Small hinge region, which allows the hemopexin domain to bring the substrate to the
active core of the catalytic domain
There is also a subfamily of the matrix metalloproteases, the membrane-type MMPs (MTMMPs) which contain an additional transmembrane domain and a short cytoplasmic domain.
After activation of MMPs by removal of the propeptide domain, their activity is regulated by
TIMPs. TIMPs specifically and reversibly inhibit the activity of MMPs. So far there have
been identified four members of the family, TIMP14. All TIMPs contain twelve conserved
cystein residues, which form six disulfide bonds. The C-terminal domains of TIMPs are
highly variable and confer their specificity towards preferred MMP targets.[3][4]

[edit] ADAM/ADAMTS

ADAM17
ADAMs comprise a family of integral membrane as well as secreted glycoproteins which are
related to snake venom metalloproteases and MMPs. Like MMPs, ADAMs are composed of
multiple conserved domains. They contain propeptide, metalloprotease, disintegrin-like,
cystein-rich, and epidermal growth factor like domains. Membrane anchored ADAMs contain
a transmembrane and cytoplasmic domain. The domains contained within the ADAMs family
have been characterized, uncovering their functional and structural roles.[5] ADAMs contain a
consensus sequence which has three histidine residues that bind to the catalytically essential
zinc ion. The propeptide is removed through cleavage by a furin type protease yielding the
active enzyme. The propeptide of most MMPs is cleavable by proteases such as trypsin,
plasmin, chymotrypsin and other MMPs.[6] ADAMs participate in a wide variety of cell
surface remodeling processes, including ectodomain shedding, regulation of growth factor
availability and mediating cell-matrix interactions. ADAM17 and ADAM15 have recently
been identified in endothelial cells (EC).[7]
ADAMTS are a subfamily of ADAM related metalloproteases that contain at least one
thrombospondin type I sequence repeat motif (TSR). They are secreted proteins; and the TSR
facilitates their localization to the ECM placing it in close proximity to their substrates.

Functionally, ADAMTS can be divided into three groups: procollagen aminopepidase,

aggrecanase, and ADAMTS13 which cleaves von Willebrand factor. Unlike with MMPs,
TIMPs are more selective in their ability to inhibit ADAMs and ADAMTSs. TIMP3 is able to
inhibit ADAM17 and 12 as well as ADAMTS4 and 5. ADAM8 and ADAM9 are not
susceptible to inhibition by TIMPs.

[edit] Other proteolytic enzymes

Many additional classes of enzymes have been identified that facilitate angiogenesis. They
include serine, aspartic, and cysteine-type proteases. A highly characterized example of the
serine protease family is the plasminogen activator-plasmin system, which has been show to
be involved in vascular remodeling. Tissue plasminogen activator (tPA), and urokinase
plasminogen activator (urokinase, uPA) are serine proteases which cleave and activate
plasminogen. The activated form of plasminogen, plasmin, is a wide ranging protease capable
of acting on various ECM components including fibrin, collagens, laminin, fibronectin, and
proteoglycans.[8] Additionally, plasmin also is able to activate various other MMPs.
In humans, the group of cathepsin cysteine proteases or cysteine cathepsins comprises 11
family members, cathepsins B, C, F, H, L1, L2, K, O, S, W, and X/Z.[9] Cysteine cathepsins
are synthesized as inactive zymogens and activated by proteolytic removal of their
propeptide. These enzymes are primarily localized in lysosomes and function in terminal
protein degradation and processing. Cathepsins also can be secreted by cells, associate with
the cell surface, and degrade the ECM. A study of all 11 members of the cathepsin family
highlights their importance in tumorigenesis and tumor associated angiogenesis.[10]
Examination of cathepsin activity by using chemical probes and in vivo imaging techniques
demonstrated an increase in cathepsin activity in the angiogenic blood vessels and invasive
fronts of carcinoma in the RIP-Tag2 transgenic mouse model of pancreatic islet tumor
genesis.
Aminopeptidases function as exopeptidases which remove amino acids from the aminoterminus of proteins. Aminopeptidase N (CD13/APN) is highly expressed on the endothelium
of growing vessels.[11] Inhibitors of CD13/APN dramatically impair tumor growth.

[edit] Ectodomain shedding

Diagram of an ectodomain shedding ADAM metalloprotease.

It has become clear in the past years that ectodomain shedding is an initial step for the
activation of specific receptors such as Notch, ErbB-4 and the angiopoietin receptor Tie-1.
Notch-1 signaling is essential for endothelial differentiation, and tumor angiogenesis, while

the angiopoietin receptor Tie-1 facilitates embryonic blood vessel formation.[12][13] Upon
binding of their ligands, Notch-1 and Tie-1 undergo proteolytic cleavage of the ectodomains
by ADAM17 and ADAM10. This cleavage frees the cytoplasmic fragment for cellular
signaling, in the case of Notch-1, it transfers to the nucleus.
Many cytokines and growth factors are synthesized as membrane bound proforms which
undergo proteolytic shedding for activation. The ephrins EPH receptor A2 and A3 are shed by
ADAM10 creating cleaved soluble Eph receptors, which inhibit tumor angiogenesis in mice.
[14]
Additional examples are the proteolytic shedding of soluble E-selectin,[15] shedding of
urokinase receptor (uPAR) by MMP-12 creating soluble uPAR which has chemotactic
properties for leukocytes and progenitor cells, and the shedding of interleukin-6 receptors by
ADAM10 and ADAM17 which facilitates interleukin-6 signaling in endothelial cells.[16]
Semaphorin 4D is cleaved from its membrane bound form by MT1-MMP (MMP-14) in
tumor cells; it then interacts with plexin B1 on endothelial cells promoting pro-angiogenic
chemotaxis.[17] Shedding of a membrane anchored cytokine or growth factor by ADAM
proteinases may be relevant for various signal transduction events. Alternatively, shedding
may be required for the ligand to diffuse to distant receptors. Shedding may be required for
the down regulation of signals by removing signaling ligands, or cleavage and release of
receptors. Release of the receptor may also generate soluble receptors which act as decoys by
sequestering ligands. These findings indicate that ectodomain shedding is a ubiquitous
process facilitating a wide variety of cellular events involved in angiogenesis. Because potent
biological modifiers are generated, it is likely controlled by highly regulated mechanism.
Along with ADAMs and MT-MMPs, membrane bound serine proteases also may play a role
in ectodomain shedding.

[edit] Proteolytic degradation of the extracellular matrix

(ECM)

Illustration depicting extracellular matrix in relation to epithelium, endothelium and

connective tissue.
The formation of capillaries from pre-existing blood vessels requires the remodeling of both
the peicapillary membrane of the parent venule, as well as the local and distal ECM. At the
onset of angiogenesis endothelial cells (EC) must remodel three different barriers in order to
migrate and invade the target tissue. First is the basement membrane between the
endothelium and vascular smooth muscle cells or pericytes, followed by the fibrin gel formed
from fibrinogen that is leaked from the vasculature, and finally the extracellular matrix in the
target tissue. The vascular basement membrane is composed of type IV collagen, type XV
collagen, type XVIII collagen, laminins, entactin, heparan sulfate proteoglycans, perlecan,
and osteonectin. All of these components of the basement membrane are substrates for MMP-

2, 3, 7, and 9, among others. Inhibitors of MMP activity have spotlighted the importance of
these proteins in controlling angiogenesis. Recently, it has been discovered that small
interfering RNA (siRNA) mediated target RNA degradation of urokinase receptor and MMP9 inhibits the formation of capillary like structures in both in vitro and in vivo models of
angiogenesis.[18] After working their way through the basement membrane, EC must invade
through a dense fibrin gel which is polymerized from fibrinogen derived from the vascular
bed.[19] Plasmin, an effective fibrinolysin produced by tPA or uPA, was thought to be essential
in this process, but plasminogen deficient mice do not display major defects of
neovascularization in fibrin rich tissues.[20] These findings highlight the diverse amount of
proteolytic enzymes ECs use to remodel the ECM. For example, MMP-3, 7, 8, 12 and 13 can
cleave fibrinogen.[21]
MMP activity is one of the earliest and most sustained processes that take place during
angiogenesis. By studying the transition from an avascular to a vascular tumor Fang et al.
were able to identify the key role of MMP-2 in angiogenesis. MMP-2 expression and activity
was increased in angiogenic tumors as compared with avascular tumors, and the addition of
antisense oligonucleotides targeting MMP-2 inhibits the initiation of angiogenesis
maintaining the avascular phenotype. This data along with other reports suggest that MMP
activity is necessary to initiate the earliest stages of angiogenesis and tumor development.
The creation of MMP deficient mice has provided important insight into the role of MMPs in
the regulation of angiogenesis. For example, MMP-2 knockout mice develop normally but
display significant inhibition of corneal angiogenesis.[22]

[edit] Proteolytic fragments as regulators of angiogenesis

Numerous proteolytic fragments or domains of ECM proteins have been reported to exert
positive or negative activity on angiogenesis. Native proteins which contain such domains
with regulatory activity are normally inactive, most likely because they are cryptic segments
hidden in the native protein structure. Angiostatin is a 38 kDa plasminogen fragment with
angiogenesis inhibitor activity. Angiostatin fragments contain kringle domains which exert
their inhibitory activity at several different levels; they inhibit endothelial cell migration and
proliferation, increase apoptosis, and modulate the activity of focal adhesion kinase (FAK).
Endostatin is a 20 kDa fragment of collagen XVIII. The major role of endostatin is in its
ability to potently inhibit endothelial cell migration and induce apoptosis.[23] These effects are
mediated by interacting and interfering with various angiogenic related proteins such as
integrins and serine/threonine-specific protein kinases. Numerous studies have demonstrated
that tropoelastin, the soluble precursor of elastin, or proteolytic elastin fragments have diverse
biological properties. Nackman et al. demonstrated that elastase generated elastin fragments
mediate several characteristic features of aneurismal disease which correlated to
angiogenesis. Osteonectin is a metal binding glycoprotein produced by many cell types
including ECs. Lastly, endorepellin is a recently described inhibitor of angiogenesis derived
from the carboxy terminus of perlecan.[24] Nanomolar concentrations of endorepellin inhibits
EC migration and angiogenesis in different in vitro and in vivo models by blocking EC
adhesion to various substrate such as fibronectin and type I collagen.
Endogenous inhibitors or activators generated by proteolytic degradation of larger proteins
mostly from the ECM have proven to contribute to the regulation of tumor growth and
angiogenesis. This article mentions only a small fraction of the known proteolytic fragments
which alter EC behavior and function during angiogenesis. This abundance has garnered
increased attention because of their potential for anti-angiogenic and anti-cancer therapies.

[edit] Proteolytic activation of growth factors

Proteases not only modulate cell-matrix interactions but also can control the onset and
progression of angiogenesis by activating angiogenic growth factors and cytokines.
Hepatocyte growth factor (HGF), an angiogenesis promoting growth factor, is activated by
HGF activation factor, a serine protease related to plasminogen.[25] Several growth factors
such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)
are trapped in the ECM by various proteoglycans. The proteolytic degradation of these
proteoglycans liberates the growth factors allowing them to reach their receptors and
influence cellular behavior. Growth factors that indirectly affect angiogenesis are also targets
of proteolytic activation. For example, plasminogen activators drive the activation of latent
transforming growth factor beta (TGF-) from bone ECM and thus modulate angiogenesis in
bone.[26]
Proteases not only have the ability change the availability of growth factors, but can also
modify their properties. This ability was shown for VEGF165 that is cleaved by MMP-3 or
MMP-9 to a smaller molecule with properties similar to VEGF121.[27] These two isoforms of
VEGF have very different properties. VEGF165 induces a regular vessel pattern during tumor
neovascularization. VEGF121 and the truncated VEGF165, in contrast, cause irregular patterns
of neovascularization, most likely due to their inability to bind heparan sulfates, wherefore
they do not provide any spatial information that is buried in the ECM. Another important
factor in angiogenesis, stromal cell-derived factor-1 (SDF-1), is also modified by the
aminodipeptidase dipeptidyl peptidase-4 (DPP4). Cleavage of SDF-1 reduces it heparan
sulfate affinity and interactions with its receptor CXCR4 are reduced.[28] The ADAM family
of proteases is receiving increased attention for their ability to alter the balance between proand anti-angiogenic factors. ADAM17 is able to release active tumor necrosis factor-alpha
(TNF) and heparin-binding EGF-like growth factor (HB-EGF) from their membrane bound
precursors which can indirectly affect angiogenesis.[29]

[edit] Proteases as inhibitors of angiogenesis

Proteases not only facilitate angiogenesis, but they also have the ability to put the brakes on
the process. One example of this is the processing of angiogenesis inhibitors by MMPs. As
previously described, MMPs have been shown to cleave plasminogen and collagen XVIII
into the endogenous angiogenesis inhibitors angiostatin and endostatin. MMP-2 itself
possesses anti-angiogenic properties that are independent of its catalytic domain. Interactions
between integrin v3 and MMP-2 on the EC cell surface may be necessary for MMP-2
activity during angiogenesis. The hemopexin like domain in the carboxy terminus of MMP-2
is able to block this interaction of active MMP-2 and integrin v3 on the EC surface which
lead to inhibition of MMP-2 activity.[30]
During angiogenesis ADAM15 is preferentially expressed on EC. ADAM15 is able to
interact with integrins v3 and 51 through its disintegrin domain via an RGD (arginineglycine-aspartic acid) motif. Most disintegrins contain this conserved RGD motif, but
ADAM15 is the only member of the ADAM family to contain this motif. A recombinant
disintegrin domain of human ADAM15 inhibits a variety of EC functions in vitro including
proliferation, adhesion, migration, and capillary formation.[31] Overexpression of ADAM15
disintegrin domain resulted in inhibition of angiogenesis, tumor growth, and metastasis. On
the other hand it has not been shown whether full length ADAM15 plays an inhibitory role in

vivo. ADAMTS1 and ADAMTS8 inhibit angiogenesis in vitro in two functional angiogenesis
assays. Both enzymes inhibit bFGF induced vascularization in the corneal pocket assay and
inhibit VEGF induced angiogenesis in the chorioallantoic membrane assay.[32] All together,
these data indicate that proteases can function as both positive and negative regulators of
angiogenesis.

[edit] Proteolysis and cell migration

Angiogenesis requires the migration and invasive growth of cells. This is facilitated by a
balanced interplay between detachment and formation of cell adhesions which enable the cell
to crawl forward through the ECM.[33] The cell uses limited proteolytic activity at sites of
individual focal adhesions via the formation of multiprotein complexes. Multiprotein
complexes are localized in lipid rafts on the cell surface, where membrane bound proteases
are often incorporated. For example, leukocytes complex urokinase (uPA), urokinase receptor
(uPAR), and integrins which participate in cell adhesion and invasion.[34] In these complexes,
uPAR acts as an organizing center forming noncovalent complexes with integrins, LRP-like
proteins, and urokinase. Similar complexes also are found on ECs.

[edit] Uncontrolled proteolysis of the ECM

The proteolytic activities that take place during angiogenesis require precise spatial and
temporal regulation. If not for this control excessive proteolysis could lead to damage of the
tissue and the loss of anchorage points for migrating cells. This is illustrated by mice which
are deficient for plasminogen activator inhibitor-1 (PAI-1).[35][36] PAI-1 inhibits plasminogen
activators and thus plasmin activation; therefore it could be assumed that PAI-1 deficiency
would increase angiogenesis and tumor growth. Unexpectedly, when PAI-1 deficient mice
were challenged with cancer cells on a collagenous matrix, angiogenesis and vascular
stabilization was inhibited, hampering tumor growth. This finding was credited to the
protective properties PAI-1 imparts against excessive degradation of the surrounding ECM by
plasmin. Without this protection the footholds used by endothelial cells to migrate and form
capillary structures are destroyed. Uncontrolled proteolysis also is attributed to the disruption
of vascular development and premature deaths in murine embryos deficient of the inhibitor
reversion-inducing-cysteine-rich protein with kazal motifs (RECK). This is most likely due to
uncontrolled MMP activity, because a partial rescue was obtained by simultaneously
knocking out RECK and MMP-2.[37]

[edit] Proteases involved in the recruitment of bone

marrow derived cells during angiogenesis
Leukocytes and endothelial progenitor cells (EPCs) contribute to the initiation and guidance
of new blood vessels.[38] Monocytes produce a variety of pro-angiogenic factors. There is also
a population of CD34 positive cells that can express endothelial associated proteins, such as
VE-cadherin and kinase insert domain receptor (KDR, VEGF receptor 2) which aid in
influencing the progression of angiogenesis.[39] The absence or dysfunction of these cells is
implicated in impaired vascularization in cardiac and diabetes patients.[40] MMP-9 plays a key
role in mobilizing EPCs from the bone marrow. Heissig et al. have proposed a mechanism for
how MMP-9 facilitates the availability of EPCs for angiogenesis. First, circulating VEGF
induces MMP-9 expression in the bone marrow, MMP-9 then is able to cleave and release c-

kit ligand. Activated c-kit is then able to recruit hematopoietic, endothelial and mast cell
progenitor cells, these cells are then accumulated in the angiogenic area and produce large
amounts of VEGF tipping the scales in favor of angiogenesis.[41]
MMP-9 is not the only protease shown to be involved in EPC enhanced angiogenesis.
Cathepsin L is active at neutral pH by associating with a p41 splice variant of the MHC class
II-associated invariant chain which is strongly expressed in EPCs.[42] This ability to stay
active at neutral pH may facilitate EPC invasion, remodeling of matrix collagens and gelatin,
and neovascularization. Knock out of cathepsin L in mice exhibited impaired blood flow
restoration in ischemic limbs, indicating impaired neovascularization. Neovascularization
also is impaired in mice treated with bone marrow derived cells deficient of cathepsin L as
compared with wild type cells. The target by which cathepsin L stimulates angiogenesis is not
yet identified.

[edit] Maturation of newly formed blood vessels via

proteases

MT1-MMP (MMP-14)
It has been well established that smooth muscle-like pericytes play an important role in
stabilizing newly formed blood vessels. Pericytes present in the stroma of tumors of breast
cancer patients express MMP-9.[43] Animal models deficient of MMP-9 display disturbed
recruitment of pericytes.[44] The inability to recruit pericytes severely affects the stability of
vessels and the degree of vascularization of neuroblastomas. Aminopeptidase A also may be
involved in pericyte recruitment due to its increased expression by activated pericytes in
various pathological conditions associated with angiogenesis.[45] The mechanism by which
this protease facilitates vessel maturation has not yet been determined. Angiogenesis requires
a fine balance between proteolytic activity and proteinase inhibition. Pericytes secrete TIMP3 which inhibits MT1-MMP dependent MMP-2 activation on endothelial cell, thus
facilitating stabilization of newly formed microvessels. Co-cultures consisting of pericytes
and endothelial cells induce the expression of TIMP-3 by pericytes, while endothelial cells
produce TIMP-2.[46] Together, these inhibitors stabilize the vasculature by inhibiting a variety
of MMPs, ADAMs, and VEGF receptor 2.
Immature vessels remain dependent on continuous exposure the angiogenic growth factors
without pericyte coverage.[47] As the reservoir of growth factors is removed the endothelial

cells do not survive, and undergo caspases induced apoptosis, while other proteases
participate in the degradation and removal of the remaining cell debris.

[edit] Perspective
Proteases play numerous roles in angiogenesis, both in development and especially in
pathological conditions. Because they are important regulators of tissue degradation and cell
migration, it is expected that their inhibition would be beneficial for inhibiting tumor growth
and vascularization. Promising results have been observed in animal studies, but clinical trials
have failed to demonstrate similar results and are often accompanied by unacceptable side
effects.[48] This has influenced continued research which has identified new families of
proteases, such as ADAM, ADAMTS, and MT-MMPs. Perhaps more significantly, a new
paradigm has emerged for proteases being essential for modulating growth factors and
cytokines, generating biologically active fragments from the matrix, facilitating recruitment
of bone marrow derived cells, and stabilization of mature blood vessels. Better understanding
of the various activities of proteases and their inhibitors will aid in more tailor made
treatments for numerous disorders.

[edit] References
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[show]v d eProteins: angiogenesis

M: anat(a:h/u/t/a/l,v:h/u/t/a/l)/phys/devp/cell noco/syva/cong/lyvd/tu
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[show]v d eHydrolase: proteases (EC 3.4)
3.4.11

Aminopeptidase (Alanine, Arginyl, Aspartyl, Cystinyl, Leucyl, Glutamyl,

Methionyl (1, 2), O)

3.4.13

Dipeptidase (1, 2, 3)

3.4.14

Dipeptidyl peptidase (Cathepsin C, Dipeptidyl peptidase-4) Tripeptidyl

peptidase (Tripeptidyl peptidase I, Tripeptidyl peptidase II)

3.4.15

Angiotensin-converting enzyme

3.4.16

Serine type carboxypeptidases: Cathepsin A DD-transpeptidase

3.4.17

Metallocarboxypeptidases: Carboxypeptidase (A, A2, B, C, E, Glutamate

II)

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Metalloexopeptidase
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[show]v d eProteases: metalloendopeptidases (EC 3.4.24)

Retrieved from "http://en.wikipedia.org/wiki/Proteases_in_angiogenesis"

Categories: Angiology | Posttranslational modification | Peptidase
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