Vasospasm

The concept of vasospasm with preeclampsia was advanced by Volhard (1918)

based on his direct observations of small blood vessels in the nail beds, ocular
fundi, and bulbar con- junctivae. It was also surmised from histological changes
seen in various affected organs (Hinselmann, 1924; Landesman, 1954).
Endothelial activation causes vascular constriction with increased resistance and
subsequent hypertension. At the same time, endothelial cell damage causes
interstitial leakage through which blood constituents, including platelets and
fibrinogen,

are deposited subendothelially. Wang and associates (2002) have also

demonstrated disruption of endothelial junctional proteins. Suzuki and coworkers
(2003) described ultrastruc- tural changes in the subendothelial region of
resistance arter- ies in preeclamptic women. The much larger venous circuit is
similarly involved, and with diminished blood flow because of maldistribution,
ischemia of the surrounding tissues can lead to necrosis, hemorrhage, and other
end-organ disturbances char- acteristic of the syndrome. One important clinical
correlate is the markedly attenuated blood volume seen in women with severe
preeclampsia (Zeeman, 2009).

■ Endothelial Cell Injury

As discussed on page 733, during the past two decades, endo- thelial cell injury
has become the centerpiece in the contem- porary understanding of preeclampsia
pathogenesis (Davidge, 2014). In this scheme, protein factor(s)—likely
placental—are secreted into the maternal circulation and provoke activation and
dysfunction of the vascular endothelium. Many of the fac- ets of the clinical
syndrome of preeclampsia are thought to result from these widespread endothelial
cell changes. Grundmann and associates (2008) have reported that circulating
endothelial cell—CEC—levels are elevated fourfold in the peripheral blood of
preeclamptic women. Similarly, Petrozella and colleagues (2012) demonstrated
increased levels of circulating endothelial microparticles—EMPs—in
preeclamptic women.

Intact endothelium has anticoagulant properties, and endo- thelial cells blunt the
response of vascular smooth muscle to agonists by releasing nitric oxide.
Damaged or activated endo- thelial cells may produce less nitric oxide and secrete
substances that promote coagulation and increase sensitivity to vasopres- sors
(Gant, 1974). Further evidence of endothelial activation includes the characteristic
changes in glomerular capillary endothelial morphology, increased capillary
permeability, and elevated blood concentrations of substances associated with
endothelial activation. These latter substances are transferable, and serum from
women with preeclampsia stimulates some of these substances in greater amounts.
It seems likely that mul- tiple factors in plasma of preeclamptic women combine
to have these vasoactive effects (Myers, 2007; Walsh, 2009).

Increased Pressor Responses

As discussed in Chapter 4 (p. 61), pregnant women normally develop
refractoriness to infused vasopressors (Abdul-Karim, 1961). Women with early
preeclampsia, however, have increased vascular reactivity to infused
norepinephrine and angiotensin II (Raab, 1956; Talledo, 1968). Moreover,
increased sensitivity to angiotensin II clearly precedes the onset of gestational
hyperten- sion (Gant, 1974).

Prostaglandins
Several prostanoids are thought to be central to preeclampsia syndrome
pathophysiology. Specifically, the blunted pressor response seen in normal
pregnancy is at least partially due to decreased vascular responsiveness mediated
by endothelial prostaglandin synthesis. For example, compared with nor- mal
pregnancy, endothelial prostacyclin (PGI2) production is decreased in
preeclampsia. This action appears to be medi- ated by phospholipase A2 (Davidge,
2014). At the same time, thromboxane A2 secretion by platelets is increased, and
the prostacyclin:thromboxane A2 ratio decreases. The net result favors increased
sensitivity to infused angiotensin II and, ultimately, vasoconstriction (Spitz, 1988).
These changes are apparent as early as 22 weeks in women who later develop pre-
eclampsia (Chavarria, 2003).

Nitric Oxide
This potent vasodilator is synthesized from l-arginine by endo- thelial cells.
Withdrawal of nitric oxide results in a clinical picture similar to preeclampsia in a
pregnant animal model (Conrad, 1989). Inhibition of nitric oxide synthesis
increases mean arte- rial pressure, decreases heart rate, and reverses the
pregnancy- induced refractoriness to vasopressors. In humans, nitric oxide likely is
the compound that maintains the normal low-pressure vasodilated state
characteristic of fetoplacental perfusion (Myatt, 1992; Weiner, 1992). It also is
produced by fetal endothelium, and here it is increased in response to
preeclampsia, diabetes, and sepsis (Parra, 2001; von Mandach, 2003).

The effects of nitric oxide production in preeclampsia are unclear (Davidge,

2014). It appears that the syndrome is asso- ciated with decreased endothelial
nitric oxide synthase expres- sion, thus increasing nitric oxide inactivation. These
responses may be race related, with African-American women producing more
nitric oxide (Wallace, 2009).

■ Endothelins
These 21-amino acid peptides are potent vasoconstrictors, and endothelin-1 (ET-1)
is the primary isoform produced by human endothelium (George, 2011). Plasma
ET-1 levels are increased in normotensive pregnant women, but women with
preeclampsia have even higher levels (Ajne, 2003; Clark, 1992). According to
Taylor and Roberts (1999), the placenta is not the source of increased ET-1
concentrations, and they likely arise from systemic endothelial activation.
Interestingly, treat- ment of preeclamptic women with magnesium sulfate lowers
ET-1 concentrations (Sagsoz, 2003).

■ Angiogenic and Antiangiogenic Proteins

Placental vasculogenesis is evident by 21 days after concep- tion. There is an ever-
expanding list of pro- and antiangio- genic substances involved in placental
vascular development. The families of vascular endothelial growth factor (VEGF)
and angiopoietin (Ang) are most extensively studied. Angiogenic imbalance is
used to describe excessive amounts of antiangio- genic factors that are
hypothesized to be stimulated by wors- ening hypoxia at the uteroplacental
interface. Trophoblast of women destined to develop preeclampsia overproduces
at least two antiangiogenic peptides that enter the maternal circulation
(Karumanchi, 2014):

1. Soluble Fms-like tyrosine kinase 1 (sFlt-1) is a variant of the Flt-1 receptor for
placental growth factor (PlGF) and for VEGF. Increased maternal sFlt-1 levels
inactivate and decrease circulating free PlGF and VEGF concentrations,

leading to endothelial dysfunction (Maynard, 2003). As shown in Figure 40-4,

sFlt-1 levels begin to increase in maternal serum months before preeclampsia is
evident. Haggerty and colleagues (2012) observed that these high levels in the
second trimester were associated with a dou- bling of the risk for preeclampsia.
This divergence from normal levels appears to occur even sooner with early-onset
preeclampsia (Vatten, 2012).

2. Soluble endoglin (sEng) is a placenta-derived 65-kDa mol- ecule that blocks

endoglin, which is a surface coreceptor for the TGFβ family. Also called CD105,
this soluble form of endoglin inhibits various TGFβ isoforms from binding to
endothelial receptors and results in decreased endothelial nitric oxide-dependent
vasodilatation (Levine, 2006; Venkatesha, 2006). Serum levels of sEng also begin
to increase months before clinical preeclampsia develops (Haggerty, 2012).

The cause of placental overproduction of antiangiogenic proteins remains an

enigma. Concentrations of the soluble forms are not increased in the fetal
circulation or amnionic fluid, and their levels in maternal blood dissipate after
deliv- ery (Staff, 2007). Research currently is focused on immuno- logical
mechanisms, oxidative stress, mitochondrial pathology, and hypoxia genes
(Karumanchi, 2014). Clinical research is directed at use of antiangiogenic proteins
in the prediction and diagnosis of preeclampsia. In a systematic review, Widmer
and associates (2007) concluded that third-trimester elevation of sFlt-1 levels and
decreased PlGF concentrations correlate with preeclampsia development after 25
weeks. These results require verification in prospective studies. Subsequently,
Haggerty and coworkers (2012) reported that doubling of expressions of sFlt-1
and sEng increased the preeclampsia risk 39 and 74 per- cent, respectively.