THE ANATOMICAL RECORD 291:699713 (2008)

Hemodynamic Changes in Splanchnic

Blood Vessels in Portal Hypertension
ISABELLE COLLE,* ANJA M. GEERTS, CHRISTOPHE VAN STEENKISTE, AND
HANS VAN VLIERBERGHE
Department of Hepatology and Gastroenterology, Ghent University Hospital,
Ghent, Belgium

ABSTRACT
Portal hypertension (PHT) is associated with a hyperdynamic state
characterized by a high cardiac output, increased total blood volume, and
a decreased splanchnic vascular resistance. This splanchnic vasodilation
is a result of an important increase in local and systemic vasodilators (ni-
tric oxide, carbon monoxide, prostacyclin, endocannabinoids, and so on),
the presence of a splanchnic vascular hyporesponsiveness toward vaso-
constrictors, and the development of mesenteric angiogenesis. All these
mechanisms will be discussed in this review. To decompress the portal
circulation in PHT, portosystemic collaterals will develop. The presence
of these portosystemic shunts are responsible for major complications
of PHT, namely bleeding from gastrointestinal varices, encephalopathy,
and sepsis. Until recently, it was accepted that the formation of colla-
terals was due to opening of preexisting vascular channels, however,
recent data suggest also the role of vascular remodeling and angiogenesis.
These points are also discussed in detail. Anat Rec, 291:699713,
2008. 2008 Wiley-Liss, Inc.

Key words: portal hypertension; splanchnic; angiogenesis;

hemodynamic

Portal hypertension (PHT) is the major hemodynamic
complication of a variety of diseases that obstruct portal
blood ow. Portal pressure gradient (DP) is the result of
portal vascular resistance (R) and portal venous inow
(Q) in analogy with Ohms law: DP = R Q. In normal
circumstances the portal pressure gradient varies
between 2 and 6 mmHg.
Two major theories were put forward to explain portal
hypertension. The backward theory assumes that the the development of portal hypertension, as a result of a
resistance to portal ow results in portal hypertension
(Benoit et al., 1985). Portal vascular resistance consists
of the sum of the serial resistance in portal vein and
intrahepatic vascular bed and of the parallel resistance
of the collaterals. The cause of enhanced vascular resist-
ance can be localized pre-, intra-, and posthepatic. Pre-
hepatic portal hypertension is mostly due to a portal
vein thrombosis and is associated with a quite normal
liver function. Posthepatically portal hypertension can
be caused, for example, by thrombosis of the hepatic
veins (Budd Chiari syndrome), occlusion of the caval
vein (web), and constrictive pericarditis. The intrahe-
patic form of portal hypertension can be subdivided into
presinusoidal (hepatic schistosomiasis, granulomatosis,
i.e., primary biliary cirrhosis and idiopathic portal
hypertension), sinusoidal (cirrhosis and brosis) and
postsinusoidal (veno-occlusive disease).
The second theory, the forward theory, proposed an
increase in portal inow as the most important factor
leading to portal hypertension (Vorobioff et al., 1984).
Portal venous inow includes the ow of the total portal
venous system and the portosystemic collaterals. During
hyperdynamic circulation caused by enhanced plasma
volume together with a decrease in the splanchnic arte-
riolar vascular resistance and an increase in cardiac out-
put, an increased blood ow in portal tributaries devel-
ops maintaining portal hypertension.
*Correspondence to: Isabelle Colle, Department of Hepatology
and Gastroenterology, Ghent University Hospital, De Pintelaan
185, 9000 Gent, Belgium. Fax: 32-9-332-49-84.
E-mail: isabelle.colle@ugent.be
Received 14 May 2007; Accepted 19 December 2007
DOI 10.1002/ar.20667
Published online in Wiley InterScience (www.interscience.wiley.
com).

2008 WILEY-LISS, INC.

700 COLLE ET AL.
Presently, the consensus is that both the rise in resist-
ance and the enhanced portal inow play an important
role in the development of portal hypertension. In this
review, we will only discuss the hemodynamic changes in
the splanchnic vascular bed and the development of portal
systemic collaterals, associated with portal hypertension.
MECHANISM OF SPLANCHNIC
HYPERDYNAMIC CIRCULATION
Portal hypertension is associated with a hyperdynamic
circulation characterized by increased cardiac output
and total blood volume in response to decreased systemic
vascular resistance (Moreau et al., 1988; Groszmann,
1993, 1994; Bosch and Garcia-Pagan, 2000; Fig. 1). This
diminished systemic vascular resistance is largely the
result of a decrease in splanchnic arterial resistance
owing to splanchnic vasodilation (Bosch and Garcia-
Pagan, 2000). At least three mechanisms have been pro-
posed to contribute to this splanchnic vasodilation in
association with portal hypertension: (1) Increased local
production of vasodilators; (2) Increased concentrations
of systemic circulatory vasodilators and; (3) Decreased
vascular response to vasoconstrictors (Groszmann and
Abraldes, 2005). Recently, a fourth mechanism of a
decrease in splanchnic arterial resistance has been pro-
posed, namely mesenteric neoangiogenesis (Fernandez
et al., 2004, 2005; Geerts et al., 2006a). Figure 1 shows
the different mechanisms playing a role in portal hyper-
tension and hyperdynamic circulation.
Increased Production of Local Vasodilators
Early local events. In the early stages of PHT,
Abraldes et al. demonstrated in rats with minimal portal
hypertension (partial portal vein ligation PPVL over a
16-gauge needle) an early increase (within 24 hr) in vas-
cular endothelial growth factor (VEGF) and endothelial
nitric oxide synthase (eNOS) expression in the jejunal
mucosal microcirculation (Abraldes et al., 2006). This
study conrms previous data in severe PHT, that up-reg-
ulation of eNOS precedes the development of splanchnic
arterial vasodilation and portal systemic shunts (Abra-
ldes et al., 2006; Wiest et al., 1999a). The up-regulation
of VEGF in the intestinal microcirculation accounts in
large part for the initial eNOS activation (Abraldes
et al., 2006). After venous pressure elevation, the redis-
tribution of ow within the bowel from the mucosa to
the muscularis may cause a certain degree of hypoxia in
the mucosa that is sufcient to stimulate VEGF produc-
tion (Granger et al., 1979, 1989; Davis and Gore, 1985).
Because mucosal arterioles account for 25% of the total
mesenteric vascular resistance, NO activation at this
level, can be the main site for the transduction of the
increased portal pressure into splanchnic vasodilation
and being the initial step in the development of the hy-
perdynamic circulation.
A second event that occurs in rats with more severe
PHT after partial portal vein ligation (PPVL over a 20-
gauge needle) is a myogenic response in the superior
mesenteric artery (SMA) as early as 10 hr after induc-
tion of PHT (Tsai et al., 2003). This SMA vasoconstric-
tion triggers eNOS catalytic activity and thus NO hyper-
production (Tsai et al., 2003). In contrast, a milder
increase in portal pressure did not result in reex SMA
vasoconstriction and eNOS was not up-regulated at the
SMA (Tsai et al., 2003).
Iwakiri et al. showed that eNOS activity was
increased before eNOS expression, suggesting activation
of eNOS at the posttranslational level (Iwakiri et al.,
2002a). This increased eNOS activity is mediated by an
Akt-dependent eNOS phosphorylation at the Serine1177
level (Iwakiri et al., 2002a). These phenomena may be
the early molecular signals that induce the cascade of
events leading to the splanchnic hyperdynamic circula-
tion.
Later local events. In PHT, once the hyperdy-
namic circulation with high cardiac output is estab-
lished, in vivo aortic levels of eNOS mRNA and eNOS
protein are increased, in response to shear stress
(Pateron et al., 2000; Tazi et al., 2002). In both studies,
treatment with propranolol signicantly decreased in
vivo aortic eNOS mRNA and protein levels (Pateron
et al., 2000; Tazi et al., 2002). Furthermore, in PHT rats
there is an increased production of NO in response to
shear stress in the superior mesenteric vascular bed
(Hori et al., 1998; Wiest et al., 1999a). In cirrhotic rat
aortas, endothelial small calcium-dependent potassium
channels (SKCa) are overexpressed and overactive in
response to shear stress, stimulating the calcium/cal-
modulin/eNOS pathway (Barriere et al., 2001). More-
over, shear stress in portal hypertensive aortas results
in activation of heat shock protein (Hsp)90, stimulating
eNOS catalytic activity. Hsp90 also contributes to the
control of the tone of the mesenteric vascular bed (Shah
et al., 1999; Tazi et al., 2002).
Intestinal bacterial translocation is common in cirrho-
sis and is followed by the production of tumor necrosis
factor alpha (TNFa) by mononuclear cells. Treatment
with noroxacin (an antibiotic that selectively decon-
taminates the intestine) in cirrhotic patients and rats
(Albillos et al., 2003; Tazi et al., 2005) decreases TNFa
production and the hyperdynamic syndrome. Further-
more, cirrhotic rats with bacterial translocation have a
more pronounced systemic and splanchnic NO overpro-
duction than those without (Wiest et al., 1999b). Both
TNFa and endotoxins may activate inducible NOS
(iNOS) and eNOS.
On one hand, cirrhotic rats have increased levels of
aortic iNOS protein which decrease after treatment with
noroxacin (Tazi et al., 2002, 2005). However, no
enhanced levels of iNOS are found in the splanchnic
vasculature of cirrhotic rats with bacterial translocation
(Wiest et al., 1999b). Thus probably has iNOS a minor
role in the development of PHT.
On the other hand, TNFa in the gastric mucosa of
portal hypertensive rats, activates Akt to phosphorylate
eNOS at the Ser1177 level leading to eNOS activation
(Kawanaka et al., 2002). Moreover, bacterial transloca-
tion stimulates the endothelial gene expression of GTP-
cyclohydrolase I, a key enzyme necessary for the produc-
tion of tetrahydrobiopterin (BH4; Wiest et al., 2003).
The BH4 production is a rate-limiting cofactor in the
NO synthesis by eNOS in the mesenteric arterial bed
(Wever et al., 1997; Wiest et al., 2003).
Recently, it has been found that neuronal NOS
(nNOS) protein expression, present in neurons and vas-
 SPLANCHNIC HEMODYNAMIC CHANGES IN PORTAL HYPERTENSION 701

Fig. 1. Mechanisms of splanchnic vasodilation and hyperdynamic circulation.

cular smooth muscle cells, is up-regulated in aorta (Xu
et al., 2000) and in mesenteric artery (Jurzik et al.,
2005; Kwon et al., 2007) of rats with cirrhosis. Neuro-
nal NOS could also play a role in the development/
maintenance of the hyperkinetic circulation (Xu et al.,
2000).
Increased Concentrations of Systemic
Circulatory Vasodilators
Recent investigations indicate that vasodilators syn-
thesized in the splanchnic circulation [nitric oxide (NO),
carbon monoxide (CO), glucagon, prostacyclin (PGI2),
702 COLLE ET AL.
vasoactive intestinal peptide (VIP), adenosine, bile salts,
platelet activating factor, substance P, calcitonin gene-
related peptide, adrenomedullin, atrial natriuretic pep-
tide, endogenous cannabinoids, and others] might be
responsible for the hyperdynamic syndrome (Moreau
and Lebrec, 1995). At the beginning of the 1990s, Val-
lance and Moncada suggested the implication of NO, a
biologically active gas, in the development of splanchnic
vasodilation and the multiple organ malfunctions that
characterize the hyperkinetic syndrome (Vallance and
Moncada, 1991). We discussed the local splanchnic pro-
duction of NO in the previous sections, while we discuss
here the systemic effects of NO and other vasodilators
present in the systemic circulation.
Nitric Oxide (NO). Most recent studies focused
their attention on the potential role of NO in the patho-
genesis of splanchnic vasodilation (Vallance and Mon-
cada, 1991; Hartleb et al., 1997; Martin et al., 1998; Liu
and Lee, 1999). Nitric oxide is a very potent vasodilator
and is synthesized by NO synthase (NOS) from the
amino acid L-arginine (Lowenstein et al., 1994). Three
different isoforms of NOS are known: neuronal (nNOS),
endothelial (eNOS), and inducible NOS (iNOS; Moncada
et al., 1997). Tonic production of NO by eNOS is believed
to play a major role in the maintenance of an active
state of vasodilation in the arterial circulation. A vast
number of studies in human and experimental cirrhosis
(Niederberger et al., 1995) suggest that NO synthesis is
increased and plays an important role in the pathogene-
sis of arterial splanchnic vasodilation.
In patients with ascites, the concentration of NO in
peripheral veins is higher than in controls and NO lev-
els in the portal vein are higher than in the peripheral
vein, suggesting that NO production is particularly
increased in the splanchnic circulation (Battista et al.,
1997). Serum nitrite and nitrate, metabolites of NO, and
the concentration of NO in exhaled air are also
increased in patients with cirrhosis and ascites (Guarner
et al., 1993; Matsumoto et al., 1995; Sogni et al., 1995).
Increased levels of NO may also play a role in the devel-
opment of hepatopulmonary syndrome (Fallon et al.,
1997). Finally, the infusion of a NOS inhibitor in a pe-
ripheral artery of cirrhotic patients with ascites partially
restores the impaired reactivity to vasoconstrictors
(Albillos et al., 1995; Campillo et al., 1995).
Among the three isoforms, eNOS activation is the
major source of NO overproduction in the splanchnic cir-
culation associated with PHT. Multiple factors such as
shear stress, inammatory cytokines (Iwakiri et al.,
2002b; Tazi et al., 2003, 2005), and vascular endothelial
growth factor (VEGF; Abraldes et al., 2006; Fernandez
et al., 2005) stimulate eNOS-dependent NO production
in PHT leading to hyperdynamic circulation.
Inducible NOS is produced in macrophages and vascu-
lar smooth muscle cells after stimulation by endotoxins
and inammatory cytokines. However, iNOS is only
detected in aorta of cirrhotic rats (Moreau et al., 2002;
Tazi et al., 2005), but not in the splanchnic vasculature
of experimental animals with PHT and cirrhosis (Cahill
et al., 1995; Martin et al., 1996; Morales-Ruiz et al.,
1996; Wiest et al., 1999b).
From recent data, there is also more evidence that
nNOS present in neurons and vascular smooth muscle
cells, can play an important role in PHT. Neuronal NOS
protein expression is up-regulated in cirrhotic rat aorta
(Xu et al., 2000) and in the mesenteric artery (Jurzik
et al., 2005; Kwon et al., 2007). Treatment with a spe-
cic nNOS inhibitor decreases the nNOS and cGMP lev-
els in the aorta and normalizes the hyperdynamic circu-
lation in cirrhotic rats, suggesting that nNOS also plays
a role in the maintenance and/or development of the
hyperkinetic mesenteric circulation (Xu et al., 2000).
Inhibition of NO production only partially inhibits and
prevents the development of portosystemic shunts and
the hyperdynamic circulation (Lee et al., 1993; Garcia-
Pagan et al., 1994; Pilette et al., 1996). This hypothesis
is supported by the study of Iwakiri et al., showing that
the hyperkinetic syndrome after portal vein ligation still
occurs in mice lacking eNOS (eNOS2/2) and also devel-
ops in double eNOS/iNOS knockout mice (Iwakiri et al.,
2002b).
Prostacyclin (PGI2). Prostacyclin (PGI2) is a
product of the metabolism of arachidonic acid by cycloox-
ygenase (COX) and causes smooth muscle relaxation by
stimulation of cyclic adenosine monophosphate (cAMP).
COX-1 is the constitutive form and COX-2 is the induci-
ble form of cyclooxygenase. Whole body production and
portal venous levels of PGI2 are increased in portal hy-
pertensive animals and cirrhotic patients and may play
a role in the splanchnic hyperemia, collateral circula-
tion, and portal hypertensive gastropathy (Sitzmann
et al., 1994; Ohta et al., 1995). Studies using inhibitors
of COX and prostacyclin suggest a pathogenetic role for
PGI2 in the hyperdynamic circulation associated with
PHT (Munoz et al., 1999; Tsugawa et al., 1999).
Carbon monoxide (CO). Carbon monoxide (CO)
is an endogenously produced gas molecule that in a
manner similar to NO, activates soluble guanylate cy-
clase leading to the generation of cGMP, which in turn
mediates various physiological functions such as smooth
muscle cell relaxation (Wang et al., 1997). CO is pro-
duced from the breakdown of heme to biliverdin and
free iron by means of the heme-oxygenase (HO) enzyme.
Like NOS, HO has three isoforms: inducible HO (HO-1)
and two constitutive forms (HO-2 and HO-3; Elbirt and
Bonkovsky, 1999).
Fernandez et al. found that HO-1 protein levels and
activity is signicantly increased in the mesentery,
spleen, intestine, and liver of portal hypertensive rats
(Fernandez and Bonkovsky, 1999; Fernandez et al.,
2001). A progressively increased expression of HO-1 is
found in mesenteric arteries, aorta and cardiac ven-
tricles from rats with secondary biliary cirrhosis (Liu
et al., 2001; Chen et al., 2004). Administration of zinc
protoporphyrin, a selective inhibitor of HO, normalizes
aortic HO activity, partially restores vascular reactivity
to vasoconstrictors and ameliorates the hyperdynamic
circulation associated with PHT (Fernandez et al., 2001;
Chen et al., 2004).
Carbon monoxide also plays a role in the pulmonary
vasodilation leading to hepatopulmonary syndrome, with
increased levels of carboxyhemoglobin in patients
with cirrhosis (Arguedas et al., 2003; Zhang et al., 2003;
De Las et al., 2003). Heme oxygenase also mediates
hyporeactivity to phenylephrine in the mesenteric
vessels of cirrhotic rats with ascites (Bolognesi et al.,
2005).
 SPLANCHNIC HEMODYNAMIC CHANGES IN PORTAL HYPERTENSION
Together with NO, carbon monoxide plays a role in
splanchnic and pulmonary vasodilation, and both can be
seen as portal hypertensive molecules. Whether HO-1
plays a role as protective antioxidant enzyme remains to
be elucidated (Moreau, 2001). The precise mechanism
whereby HO-1 gene expression is induced is still
unknown. However several physical and chemical fac-
tors that are present during portal hypertension, includ-
ing cytokines, endotoxins, and shear stress, can activate
HO-1 transcription (Elbirt and Bonkovsky, 1999; Bosch
and Garcia-Pagan, 2000).
Endocannabinoids. Anandamide is an endoge-
nous lipid ligand that through binding with its cannabi-
noid CB1 receptor leads to hypotension. Monocytes from
cirrhotic patients and rats contain increased levels of
anandamide (Batkai et al., 2001; Ros et al., 2002).
Thereby, mesenteric vascular CB-1 receptors are maxi-
mally activated in cirrhosis (Batkai et al., 2001; Ros
et al., 2002).
Administration of a CB1 receptor antagonist SR
141716A increases mean arterial pressure (Batkai et al.,
2001; Ros et al., 2002), peripheral resistance (Ros et al.,
2002), and vascular tone in the mesenteric artery
(Domenicali et al., 2005) and decreases portal hyperten-
sion and mesenteric blood ow in cirrhotic rats (Batkai
et al., 2001). Activation of CB-1 receptors may lead on
one hand to eNOS stimulation and production of NO
and on the other hand to potassium channel activation,
both leading to vasodilation (Batkai et al., 2001; Ros
et al., 2002; Howlett et al., 2002).
Endothelium-derived hyperpolarizing factor
(EDHF). In normal arterial walls exposed to NOS/cy-
clooxygenase (COX)-inhibitors, acetylcholine or shear
stress induce the release of an endothelium-derived
relaxing factor (EDRF; Cohen and Vanhoutte, 1995).
This NOS/COX independent EDRF has been called
endothelium-derived hyperpolarizing factor or EDHF,
because it induces hyperpolarization and arterial vascu-
lar smooth muscle cell relaxation (Cohen and Vanhoutte,
1995). The exact nature of EDHF is controversial; how-
ever, the main molecules considered to explain EDHF-
mediated vasodilation are monovalent cation potassium,
arachidonic acid metabolites, components of gap junc-
tions, and hydrogen peroxidase (Iwakiri and Groszmann,
2006). EDHF is more prominent in smaller arteries and
arterioles than in larger arteries, and its role becomes
more important in the absence of NO (Iwakiri and
Groszmann, 2006). Thus, the presence of EDHF can
explain why hyperdynamic circulation still develops in
portal hypertensive eNOS/iNOS knockout mice (Iwakiri
et al., 2002b).
In cirrhotic rats, EDHF is released by the superior
mesenteric artery but not in the aorta (Barriere et al.,
2000). In this cirrhotic mesenteric artery, EDHF-induced
smooth muscle cell relaxation is abolished by a combina-
tion of apamin and charybdotoxin and decreased by bar-
ium or ouabain (Barriere et al., 2000). Thus, in the supe-
rior mesenteric artery from cirrhotic rats, EDHF may be
a K1 ion released by endothelial apamin- and charybdo-
toxin sensitive K1 channels, K1 then activating barium
sensitive K1 channels and Na1/K1 ATPase in the
smooth muscle cells leading to hyperpolarization and
relaxation of the vascular wall (Barriere et al., 2000).
703
Moreover, it has been shown that endothelial small-
conductance Ca11-dependent K1 (SK1Ca) channels are
overexpressed in cirrhotic aortas (Barriere et al., 2001a).
In cirrhosis, selective SK1Ca channel blockade by apa-
min results in a decreased eNOS hyperactivity and NO-
dependent smooth muscle relaxation (Barriere et al.,
2001). Thus, in cirrhotic arterial walls, activation of K1
channels located in the plasma membrane of endothelial
and smooth muscle cells, induces membrane hyperpolar-
ization, which may contribute to systemic and splanch-
nic arterial vasodilation.
Hydrogen sulfate (H2S). Recently it has been
suggested that H2S is a potent endogenous vasodilator
(derived from L-cysteine) in mesenteric arteries and
aorta (Hosoki et al., 1997; Zhao and Wang, 2002; Cheng
et al., 2004). This H2S-mediated vasodilation occurs by
means of opening of K1ATP channels and thus independ-
ently of the cGMP pathway (Zhao et al., 2001). The role
of H2S is postulated in the vascular abnormalities seen
in cirrhosis; however, more studies are needed to con-
rm this hypothesis (Ebrahimkhani et al., 2005).
Other systemic vasodilators. In portal hyper-
tension, despite NOS and COX inhibition, arterial vaso-
dilation, and vascular hyporeactivity are not totally sup-
pressed, suggesting the presence of NOS/COX independ-
ent vasodilators (Moreau and Lebrec, 1995). Increased
plasma levels of natriuretic peptides, glucagon, adreno-
medulin, calcitonin gene-related peptide, substance P,
and vasoactive intestinal peptide have been described in
cirrhosis (Moreau and Lebrec, 1995, 2005). Probably,
other vasodilators will be discovered in the future.
Vascular Hyporesponsiveness to
Vasoconstrictors
In cirrhosis and portal hypertension, the presence of
splanchnic vasodilation in the face of highly elevated
levels of circulating vasoconstrictors (angiotensin II, nor-
epinephrin, endothelin, vasopressin, and so on), can be
explained by vascular hyporesponsiveness. This splanch-
nic resistance to vasoconstrictor agents (Lee et al., 1992;
Sieber et al., 1993) explains why the hyperdynamic cir-
culation increases with progression of the disease de-
spite the stimulation of renin-angiotensin, sympathetic
nervous system, and vasopressin release. In contrast,
these systems induce vasoconstriction in other organs,
such as the brain and kidneys in patients with ascites
(Fernandez-Seara et al., 1989; Guevara et al., 1998;
Maroto et al., 1993; Maroto et al., 1994).
A large number of studies have described hyporespon-
siveness in cirrhosis and portal hypertension to different
vasoconstrictors (methoxamine, potassiumchloride, phe-
nylephrine, terlipressin, vasopressin, endothelin-1, an-
giotensin-II, norepinephrine; Michielsen et al., 1995a;
Atucha et al., 1996; Sogni et al., 1996, 1997; Heinemann
et al., 1997; Schepke et al., 2001; Chu et al., 2000;
Barriere et al., 2001; Colle et al., 2004b). Arterial hypo-
reactivity to vasoconstrictors may also differ from one
vascular bed to another: in cirrhotic rats vascular hypo-
responsiveness occurs in the superior mesenteric artery
and in the aorta, but is normal in carotid artery
(Pateron et al., 1999).
704 COLLE ET AL.
The increased concentrations of local and systemic
vasodilators (NO, HO, and adrenomedullin) as described
above, are probably the cause of this hyporeactivity
(Kojima et al., 2004; Bolognesi et al., 2005; Erario et al.,
2005). However, the molecular mechanisms of this vas-
cular hyporesponsiveness are not well understood and
are multiple (Bomzon and Huang, 2001; Moreau, 2001).
Vascular hyporeactivity to most relevant endogenous
vasoconstrictors in the hepatic artery of cirrhotic
patients is not caused by a down regulation of a1-adre-
noreceptors a, b, and c; angiotensin II receptor I; vaso-
pressin V1a receptor, and endothelin A and B receptors.
These vasoconstrictor receptors are even up-regulated in
the hepatic artery (Neef et al., 2003).
Under normal conditions, splanchnic arterioles are
partially constricted and have the capacity to either fur-
ther constrict or dilate. The basal contractile state (tone)
of arteriolar smooth muscle cells reects the balance of
multiple inuences that either cause relaxation or con-
striction of the vascular smooth muscle cell. Important
vasoconstrictors inuencing splanchnic arterioles
include some circulating agents (e.g., angiotensin II),
myogenic factors, certain endothelium-derived substan-
ces (e.g., endothelin), and some neurotransmitters (e.g.,
norepinephrine). All vasoconstrictor receptors belong to
the superfamily of guanine nucleotide-binding protein
(G-protein) -coupled receptors (GPCR). Stimulation of
GPCR on the vascular smooth muscle cell activates G
proteins and consequently phospholipase C (PLC) -b. PLC
hydrolyzes phosphatidylinositol 4,5-biphosphate into ino-
sitol triphosphate (IP3) and diacylglycerol (DAG). IP3
diffuses in the cytosol and DAG remains in the plasma
membrane activating protein kinase C (PKC). Both
products cause an increase in intracellular calcium in
the vascular smooth muscle cell. The released calcium
initiates a cascade of intracellular events, resulting in
cross bridging of actin and myosin, leading to contrac-
tion (Bomzon and Huang, 2001; Cahill et al., 2001).
Figure 2 shows schematically the mechanism of vasocon-
striction.
Different possible mechanisms contribute to this hypo-
reactivity to vasoconstrictors. In normal circumstances
NO stimulates the production of cGMP which activates
cGMP dependent serine-threonine protein kinase called
PKG (Lincoln and Cornwell, 1993). PKG inhibits the remodeling process, in which growth, migration and
GPCR signaling pathway used by vasoconstrictors at dif-
ferent levels: (1) PKG increases GTPase activity termi-
nating vasoconstrictor signalling (Tang et al., 2003); (2)
PKG may phosphorylate GPCR and thus uncouple the
receptor and G-proteins (Lincoln and Cornwell, 1993;
Moreau and Lebrec, 2005).
In portal hypertension, there is a decreased ex vivo
production of IP3 and DAG in response to vasoconstric-
tors using GPCR in portal hypertensive arteries (Moreau
and Lebrec, 1995). Also ex vivo enzymatic activities of
PKC-a and PKC-d are decreased in cirrhotic vascular
smooth muscle cells (Tazi et al., 2000). Moreover, in vivo
PKC-a protein levels are decreased in portal hyperten-
sive aortas (Moreau and Lebrec, 1995; Bomzon and
Huang, 2001). In endothelium-denuded hepatic arteries
from cirrhotic patients, ex vivo exposure to different vas-
oconstrictors shows hyporeactivity to some but not to
others (Heller et al., 1999).
These results suggest that both effects of vasodilators
on the vasoconstrictive system, but also that abnormal-
ities within the smooth muscle and endothelial cells may
be responsible for this vascular hyporesponsiveness to
vasoconstrictors. This has been extensively reviewed in
two articles of Cahill et al. and Bomzon et al. (Bomzon
and Huang, 2001; Cahill et al., 2001).
Recently, the presence of neuropeptide Y1 (NPY) in
the superior mesenteric artery in PHT was observed.
NPY becomes increasingly important and increased
release of NPY may represent a compensatory mecha-
nism to counterbalance arterial vasodilation by restoring
the efcacy of endogenous cathecholamines, especially in
states of high levels of alfa1-adrenergic activity (Wiest
et al., 2006, 2007).
Vascular Responsiveness to Vasodilators
While for most vasoconstrictors there is an impaired
vascular response, conicting results concerning the
response (hypo-, hyper-, and normal response) of the
splanchnic vascular bed to different vasodilators have
been reported (Tables 1 and 2). By using endothelium-
dependent (acetylcholine) and -independent agents
[pinacidil, potassium ATP (KATP) channel opener; deta-
NONOate and sodiumnitroprusside as NO donors], the
integrity of the endothelium and the vascular smooth
muscle cell can be evaluated. Figure 3 shows a simpli-
ed scheme of different action mechanisms of vasoactive
agents. Our group found also an in vivo hyporeactivity
of the mesenteric vascular bed for acetylcholine, pinaci-
dil, detaNONOate and sildenal, which persisted after
NOS and COX inhibition (Colle et al., 2004a,b). Hyper-
response to vasodilators can contribute to further
splanchnic vasodilation, while hyporesponse to vasodila-
tors can be seen as a defence against further aggrava-
tion of the hyperdynamic circulation.
Increased Splanchnic Angiogenesis
Introduction to angiogenesis. During embryo-
genesis and organogenesis blood vessel formation occurs
by aggregation of de novo forming angioblasts or endo-
thelial progenitor cells into a primitive vascular plexus
(vasculogenesis), which then undergoes a complex
sprouting lead to the development of a functional circu-
latory system (angiogenesis; Carmeliet, 2000). During
adulthood in normal situations, angiogenesis occurs only
in the cycling ovary and in the placenta during preg-
nancy. In pathological situations in response to hypoxia
and/or inammation, angiogenesis is reactivated during
wound healing and repair. However, this stimulus can
become excessive, and the balance between stimulators
and inhibitors turns to a pathological angiogenic switch
(best known condition is malignant tumor formation)
(Carmeliet, 2000, 2003).
The vascular endothelial growth factor (VEGF) family
and their VEGF receptors (VEGFRs) are considered as
the most important factors involved in angiogenesis and
receive thereby most of the attention in the current lit-
erature (Carmeliet, 2003; Ferrara et al., 2003). VEGF-A
has been recognized as the major relatively specic
growth factor for endothelial cells and exhibits two
major biological activities: rst is the capacity to stimu-
late vascular endothelial cell proliferation, and second is
 SPLANCHNIC HEMODYNAMIC CHANGES IN PORTAL HYPERTENSION 705

Fig. 2. Vasoconstriction: Schematic presentation of the interactions between endothelial and smooth
muscle cell.

the ability to increase vascular permeability (Carmeliet, an important role in pathological circumstances. Loss of
2000, 2003). PlGF impairs angiogenesis in the ischemic retina, limb,
In addition to VEGF, placental growth factor (PlGF), heart, wounded skin, and in cancer, whereas administra-
originally discovered in human placenta in 1991, plays tion of recombinant PlGF (rPlGF) promotes collateral
706 COLLE ET AL.

TABLE 1. Different reactivities in response to acetylcholine

Model Methods Author Reference

Hyporeactivity CBDL Aortic and SMA rings Barriere 2001
PPVL Aortic rings Atucha 1996
CCl4
PPVL Aortic rings Karatapanis 1994
PPVL Aortic rings Michielsen 1995a
CBDL Aortic rings Rastegar 2001
CBDL Mesenteric superior artery Colle 2004a
PPVL
Hyperreactivity Human Forearm Albillos 1995
PPVL Preconstricted Aortic rings Gadano 1999
PPVL Preconstricted isolated perfused SMA Heinemann 1996
Normal reactivity CBDL Pulmonary artery Chabot 1996
PPVL Preconstricted renal artery Garcia-Estan 1996
CCl4 Isolated perfused SMA Mathie 1996
PPVL 6m Isolated Aortic rings Michielsen 1995b
CBDL Preconstricted Aortic rings Ortiz 1996
PPVL Preconstricted SMA rings Sogni 1996
CBDL Preconstricted Aortic rings Sogni 1997
SMA 5 superior mesenteric artery; CBDL 5 common bile duct ligation; PPVL 5 partial portal vein ligation; CCl4 5 carbon
tetrachloride.

TABLE 2. Different reactivities in response to other vasodilators than acetylcholine

Model Method Substance Author Reference

Hyporeactivity CBDL Gastric blood ow in vivo Nitroprusside Geraldo 1996
CCl4 Isolated perfused SMA Nitroprusside Mathie 1996
CBDL Hemodynamics Nitroprusside Safka 1997
CBDL Hemodynamics Prostacyclin Safka 1997
CBDL Hemodynamics Prostacyclin Oberti 1993
PPVL
CBDL Hemodynamics Aprikalim Safka 1997
CBDL Hemodynamics Diltiazem Safka 1997
Human Hepatic artery Isoproterenol Heller 1999
PPVL Mesenteric vein Salbutamol Martinez-Cuesta 1996
CBDL Hemodynamics and isolated SMA VIP Lee 1996
CBDL Superior mesenteric artery Pinacidil Colle 2004a
PPVL DetaNONOate
CBDL SMA Sildenal Colle 2004b
Hyperreactivity PPVL Preconstricted aortic rings NaF Hou 1997
PPVL Preconstricted isolated perfused SMA SIN1 Heinemann 1996
Human Portal vein Isoproterenol Heller 1999
Normal reactivity PPVL Perfused mesenteric bed Nitroprusside Atucha 1996
CBDL
Human Forearm Nitroprusside Albillos 1995
CBDL Pulmonary artery Nitroprusside Chabot 1996
PPVL Preconstricted renal artery Nitroprusside Garcia-Estan 1996
CBDL Aortic rings Nitroprusside Rastegar 2001
CBDL Hemodynamics Nicardipine Safka 1997
CBDL Hemodynamics Verapamil Safka 1997
PPVL Preconstricted isolated perfused SMA Foskolin Heinemann 1996
PPVL Aortic rings Glycerilnitrate Karatapanis 1994
SMA 5 superior mesenteric artery; CBDL 5 common bile duct ligation; PPVL 5 partial portal vein ligation; CCl4 5 carbon
tetrachloride; VIP 5 vasoactive intestinal peptide; NaF 5 sodium uoride; SIN 1 5 3-morpholino-sydnonimine (NO donor).

vessel growth in models of myocardial and limb ischemia
(Carmeliet et al., 2001; Carmeliet, 2003; Autiero et al.,
2003).
Three receptor tyrosine kinases, binding the VEGF
family members have thus far been identied. VEGF
receptor-1 (or Flt-1, Fms-like tyrosine kinase-1) binds
VEGF-A and PlGF; VEGF receptor-2 (or Flk-1, fetal
liver kinase-1) binds VEGF-A and VEGF-C and VEGF
receptor-3 (or Flt-4) binds VEGF-C. The major mediator
of the mitogenic, angiogenic, and permeability-enhanc-
ing effects of VEGF-A is VEGFR-2 (Carmeliet et al.,
2001, 2003; Autiero et al., 2003).
Role of VEGF in splanchnic hyperdynamic cir-
culation. Fukumura et al. demonstrated that VEGF
induces NO production by means of activation of eNOS
protein expression and activity (Fukumura et al., 2001).
Recently, Abraldes et al. showed that VEGF up-regula-
 SPLANCHNIC HEMODYNAMIC CHANGES IN PORTAL HYPERTENSION
tion in the intestinal mucosal microcirculation accounts
largely for the initial eNOS up-regulation in mild PHT,
which precedes the development of vasodilation and the
development of portosystemic shunting in mild PHT
(Abraldes et al., 2006). Moreover, our group also found
increased levels of VEGF in mesenteric tissue of rats
with PHT and cirrhosis (Geerts et al., 2006a). This was
associated with an increased vascular permeability, only
detected in cirrhotic rats but not in pure portal hyper-
tensive rats (Geerts et al., 2006a).
Role of angiogenesis in splanchnic hyperdy-
namic circulation. Nevertheless, these functional
alterations (especially vasodilation) described above can
not fully explain the observed sustained splanchnic vaso-
dilation. In addition to these functional changes, prob-
ably also structural vascular changes are implicated in
portal hypertension.
Previous studies provided evidence for increased
angiogenesis and VEGF production in the splanchnic
territory of portal hypertensive rats and cirrhotic
patients (Perez-Ruiz et al., 1999; Sumanovski et al.,
1999; Cejudo-Martin et al., 2001; Sieber et al., 2001).
Recently, our group was able to show an in vivo
increased angiogenesis in the mesenteric microcircula-
tion of rats with PHT with and without cirrhosis (Fig.
4)(Geerts et al., 2006a). This increased mesenteric angio-
genesis was associated with an increased VEGF and
eNOS protein expression (Geerts et al., 2006a). We could
also demonstrate that neo-angiogenesis is present in the
mesentery of portal hypertensive mice, and is associated
with an up-regulation of VEGF and PlGF protein levels
in the mesentery (Geerts et al., 2006a,b)(both oral pre-
sentations). PlGF knockout (PlGF2/2) portal hyperten-
sive mice do not develop neo-angiogenesis in the mesen-
tery and have lower portal venous pressures compared
with the control portal hypertensive mice (Geerts et al.,
2006a,b).
These ndings conrm the assumption that chronic
portal hypertension induces structural, as well as the
well-described functional vascular changes. Sieber dem-
onstrated that this increased mesenteric angiogenesis
could be reversed by chronically inhibiting NO formation
(Sieber et al., 2001).
Recently, Fernandez et al. showed that blocking of the
VEGF-receptor 2 signaling pathway in portal vein-ste-
nosed mice and rats (using anti-VEGFR-2 monoclonal
antibodies or using VEGFR-2autophosphorylation inhi-
bition, both for 57 days after surgery) resulted in a sig-
nicant decrease in the number of mesenteric blood ves-
sels (shown by splanchnic protein levels of CD31) and
VEGFR2 protein expression (Fernandez et al., 2004,
2005). These results were accompanied by an increase in
splanchnic arteriolar and portal venous resistance
resulting in a decreased portal venous inow, however,
portal pressure remained high (Fernandez et al., 2004,
2005). These studies further contribute to the hypothesis
that a decrease in VEGF- and PlGF-dependent angio-
genesis could reduce vascular density, splanchnic blood
ow and thus portal venous inow in partial portal vein-
ligated animals (Fernandez et al., 2004, 2005; Geerts
et al., 2006b).
The mechanisms by which VEGF protein expression
in portal hypertension is increased are probably multi-
factorial. Indeed, several factors relevant to the pathoge-
707
nesis of portal hypertension, such as hypoxia, cytokines,
and mechanical stress, have been shown to promote
VEGF expression in various cell types and tissues (Car-
meliet, 2000, 2003). We can assume that increased por-
tal pressure (even if it is minimal) is the initial factor
that triggers VEGF and eNOS expression in the portal
system (Abraldes et al., 2006), which is followed by
increased blood ow further exaggerating VEGF overex-
pression, resulting in enhanced angiogenesis. Recently, a
role for NAD(P)H oxidase (a major source of reactive ox-
ygen species) and for the enzyme heme-oxygenase-1
(HO) was suggested to contribute to the angiogenic stim-
ulus in PHT (Abraldes et al., 2006; Angermayr et al.,
2006, 2007). Chronic HO inhibition signicantly
decreased VEGF protein expression in the mesentery of
portal hypertensive rats, suggesting that HO enzymatic
activity is an important stimulus for VEGF production
in portal hypertension (Angermayr et al., 2006). Also,
hypoxia inducible factor (HIF) plays probably an initiat-
ing role in the activation of VEGF.
Role of angiogenesis in other organs associ-
ated with PHT. Besides mesenteric angiogenesis
there is evidence for up-regulation of angiogenic factors
in other splanchnic organs. In patients and in animal
models there is an increased expression of VEGF in por-
tal hypertensive gastric mucosa and can be involved in
the development of portal hypertensive gastropathy
(Tsugawa et al., 2000, 2001). Moreover, Yin et al. demon-
strated higher levels of VEGF in the esophagus of portal
hypertensive rats (Yin et al., 2005). At this moment, this
domain needs further investigation.
COLLATERAL CIRCULATION
The development of portal hypertension is associated
with changes in both the venous and arterial splanchnic
circulation. In the venous circulation, portosystemic col-
laterals are formed which cause shunting of blood from
the portal to the systemic circulation. The development
of portosystemic shunts, as a compensatory mechanism
to decompress the portal circulation and pressure, is re-
sponsible for major complications such as encephalop-
athy, sepsis and bleeding from gastrointestinal varices.
At the arterial side, there is an important vasodilation
increasing portal venous inow. By this mechanism, por-
tal pressure remains high, despite the formation of an
extensive network of collaterals.
Until recently, it was thought that the development of
collateral circulation was due to the opening of pre-
existing vascular channels in response to increased
portal pressure, a physiological process which includes
NO-mediated vasodilation activated by shear stress and
VEGF. Accordingly, all therapeutic strategies are aimed
to decrease portal blood inow and thus pressure. Porto-
systemic shunting was inhibited by NOS inhibitors in
portal vein stenosed rats (Mosca et al., 1992; Lee et al.,
1993; Chan et al., 1999). Nonselective b-blockers not
only reduce cardiac output but also constrict the collat-
eral circulation (azygos blood ow; Cales et al., 1985a,b)
leading to a decreased portal pressure. The administra-
tion of propranolol also decreases shear stress and con-
sequently attenuates eNOS production and systemic
arterial vasodilation (Tazi et al., 2002).
708 COLLE ET AL.

Fig. 3. Vasodilation: Schematic presentation of the interactions between endothelial and smooth mus-
cle cell.
 SPLANCHNIC HEMODYNAMIC CHANGES IN PORTAL HYPERTENSION
Fig. 4. Intravital microscopy images of the microvascular density in
the mesentery of Sham-operated rats (control rats), portal hyperten-
sive rats (induced by partial portal vein ligation, PPVL), and cirrhotic
rats (induced by common bile duct ligation, CBDL). In Sham rats, a
normal vasculature is present. In portal hypertensive and cirrhotic rats,
the vascular network is irregular and dense arranged. Areas of intense
capillary proliferation are seen.
However, not only vasodilation of pre-existing vessels
may be involved in collateral formation, but also vascu-
lar remodelling as a long term adaptive response to
allow chronic increased blood ow and pressure. In blood
vessels of cirrhotic rats, there is a decreased wall thick-
709
ness, which is reversed by NOS inhibition (Fernandez-
Varo et al., 2003).
Finally, recent evidence shows the predominant role
for angiogenic processes in collateral vessel formation
(Fernandez et al., 2004, 2005). Angiogenesis is mostly
dependent on VEGF, the major growth factor for blood
vessels. VEGF acts through NO-dependent mechanisms
as NO is an important downstream mediator of VEGF
that facilitates vasodilation and endothelial cell prolifer-
ation and migration (Carmeliet, 2000; Fukumura et al.,
2001). Additionally, NO also stimulates the release of en-
dothelial progenitor cells from the bone marrow, thereby
contributing to vasculogenesis, necessary for the synthe-
sis of de novo vessels (Carmeliet, 2000; Urbich and
Dimmeler, 2004). Experimental inhibition of NO forma-
tion appears to antagonize the angiogenic response and
to reduce ow and shunting through existing portal-sys-
temic collateral vessels (Sumanovski et al., 1999; Sieber
et al., 2001). Mechanical forces, most notably shear stress,
but also endotoxemia both stimulate NO generation and
are thus important in collateral vessel formation.
The implication of VEGF/VEGFR-2 pathway in angio-
genesis and the formation of collateral circulation was
supported by two studies of Fernandez et al. (2004,
2005). The administration of a monoclonal antibody
against VEGF-receptor 2 and an inhibitor of VEGF re-
ceptor-2 activation, both resulted in a 50% decrease in
the formation of portal-systemic collateral vessels in por-
tal hypertensive animal models (Fernandez et al., 2004,
2005). Both studies suggest that VEGFR2-mediated
angiogenesis plays an important role in the development
of portosystemic shunts and hyperdynamic splanchnic
circulation. Importantly, in both studies the portal pres-
sure remained high in portal hypertensive animals de-
spite reduction in mesenteric blood ow. The increase in
arterial mesenteric and portal venous resistance, caused
possibly by diminishing the number of splanchnic blood
vessels and collaterals can be the cause of this phenom-
enon. So, decreased mesenteric blood ow and increased
splanchnic vascular resistance results in almost no
change in portal pressure.
CONCLUSIONS
In conclusion, portal hypertension is a result of an
increased portal blood inow and increased portal resist-
ance. The increased portal blood ow is due to a process
of splanchnic vasodilation and mesenteric neo-angiogen-
esis. The splanchnic vasodilation is due to (1) Increased
splanchnic arterial eNOS-mediated NO production; (2)
Increased iNOS and nNOS-mediated NO production and
release of other systemic vasodilators such as endocan-
nabinoids, CO, prostaglandins, glucagons, and others;
(3) Hyporesponsiveness of the splanchnic vascular bed
toward vasoconstrictors; and nally (4) Mesenteric
angiogenesis mediated by vascular endothelial growth
factor and placental growth factor.
Portosystemic collateral formation related to portal
hypertension is a result of the dilation of pre-existing
blood vessels, vascular remodeling, and also neo-angio-
genesis. Endothelial NOS and VEGF appear to be two
important players in these events.
Inhibition of splanchnic angiogenesis can be a novel
approach to prevent the complications of portal hyper-
tension such as formation of a collateral circulation
710 COLLE ET AL.
(varices, encephalopathy) and splanchnic vasodilation,
thereby reducing morbidity and mortality in patients
with chronic liver diseases. However, further studies are
needed to explore if other proangiogenic factors (e.g.,
PLGF, and so on) and receptors (VEGFR1, and so on)
are involved in portal hypertension.
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