First, soluble ins-like yrosine kinase i {sFlt-i} is a receptor for VEGF. As depicted in Figure 40-3, elevated maternal sFlt-1 levels inactivate and reduce circulating free placental growth factor (PIGF) and VEGF concentrations, leading to endothelial dysfunction (Maynard, 2003). Importantly, sFlt-1 levels begin to rise in maternal serum months before preeclampsia is evident (Fig. 40-4). These high levels in the second trimester are associated with a doubling of the risk for preeclampsia (Haggerty, 2012). This divergence from normal levels appears to develop even sooner with early-onset preeclampsia (Vatten, 2012). These factors are also operative in pregnancies complicated by fetal-growth restriction (Herraiz, 2012).
A second antiangiogenic peptide, soluble endoglin (sEng), inhibits various transforming growth factor beta (TGF-3) isoforms from binding to endothelial receptors (see Fig. 40-3). Endoglin is one of these receptors. Decreased binding to endoglin diminishes endothelial nitric oxide-dependent vasodilatation. Serum levels of sEng also begin to rise months before clinical preeclampsia develops (Haggerty, 2012). Interestingly, metformin reduces antiangiogenic secretion from human tissues (Brownfoot, 2016).
In one systematic review, third-trimester elevation of sFlt-1 levels and lower PIGF concentrations correlate with and soluble endoglin (sEng).
preeclampsia development after 25 weeks' gestation (Widmer, 2007). Subsequently, Haggerty and coworkers (2012) reported that doubling of expressions of sFlt-1 and sEng increased the preeclampsia risk by 39 and 74 percent, respectively. The cause :J• :JE
FIGURE 40-4 Angiogenic and antiangiogenic factors in normotensive (N) and preeclamptic (PE) women across pregnancy. Both pairs of factors are significantly divergent by 23 to 26 weeks' gestation. sFlt = soluble fms-like tyrosine kinase 1; PIGF = placental growth factor. (Data from Myatt, 201o3.) of placental overproduction of anti angiogenic proteins remains an enigma. here is a racial-ethnic diference in their secretion (Yang, 2016). Concentrations of the soluble forms are not higher in fetal circulation or amnionic fluid of preeclamptic women, and their levels in maternal blood dissipate after delivery (Staf, 2007).
Clinical research aims to employ antiangiogenic proteins in the prediction and diagnosis of preeclampsia. One preliminary report described therapeutic apheresis to reduce sFlt-1 levels (Thadhani, 2016).
Evidence for preeclampsia manifestation begins early in pregnancy with covert pathophysiological changes that gain momentum across gestation and eventually become clinically apparent. Unless delivery supervenes, these changes ultimately lead to multiorgan involvement with a clinicl spectrum ranging from meager findings to one of cataclysmic deterioration. As discussed, these are thought to be a consequence of endothelial dysfunction, vasospasm, and ischemia. Although the many maternal consequences of the preeclampsia syndrome are usually described in terms of individual organ systems, they frequently are multiple and overlap .