As discussed in Chapter 4 (p. 63), pregnant women normally develop refractoriness to infused vasopressors (AbdulKarim, 1961). Women with early preeclampsia, however, have enhanced vascular reactivity to infused norepinephrine and angiotensin II (Raab, 1956; Talledo, 1968). Moreover, increased sensitivity to angiotensin II clearly precedes the onset of gestational hypertension (Gant, 1974). Paradoxically, women who develop preterm preeclampsia have lower circulating levels of angiotensin II (Chase, 2017).
Several prostaglandins are thought to be central to preeclampsia syndrome pathophysiology. Specifically, the blunted pressor response seen in normal pregnancy is at least partially due to diminished vascular responsiveness mediated by endothelial prostaglandin synthesis. For example, compared with normal pregnancy, endothelial prostacyclin (PGI2) production is lower in preeclampsia. This action appears to be mediated by phospholipase A2 (Davidge, 2015). At the same time, thromboxane A2 secretion by platelets is increased, and the prostacyclin:thromboxane A2 ratio declines. The net result favors greater sensitivity to infused angiotensin II and, ultimately, vasoconstriction (Spitz, 1988). hese changes are apparent as early as 22 weeks' gestation in gravidas who later develop preeclampsia (Chavarria, 2003).
Nitric oxide is a potent vasodilator synthesized from I-arginine by endothelial cells. Inhibition of nitric oxide synthesis raises mean arterial pressure, lowers 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). he efects of nitric oxide production in preeclampsia are unclear. It appears that the syndrome is associated with decreased endothelial nitric oxide synthase expression, thus resulting in lower nitric oxide activity (Davidge, 2015).
Endothelins are 21-amino-acid pep tides and potent vasoconstrictors. Endothelin-1 (ET -1) is the primary isoform produced by human endothelium (Karumanchi, 2016b). Plasma ET-1 levels are elevated in normotensive pregnant women, but women with preeclampsia have even higher levels (Ajne, 2003). 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, treatment of preeclamptic women with magnesium sulfate lowers ET -1 concentrations (Sagsoz, 2003). And, in animal studies, sildenafil reduces ET-1 concentrations (Gillis, 2016).
Placental vasculogenesis is evident by 21 days after conception. The list of pro-and antiangiogenic substances involved in placental vascular development is extensive, and the families of vascular endothelial growth factor (VEGF) and angiopoietin are the most studied. Angiogenic imbalance describes excessive amounts of antiangiogenic factors, which are thought to be stimulated by worsening hypoxia at the uteroplacental interface. Trophoblast of women destined to develop preeclampsia overproduces at least two antiangiogenic pep tides that enter the maternal circulation (Karumanchi, 20 16a).