Impaired Microvascular Endothelial Function in Preeclampsia

Abstract

Rational Women with preeclampsia (PE) have compromised endothelial function (assessed by brachial artery flow‐mediated dilation) compared to normal women. Placental and uterine spiral artery endothelial dysfunction is seen in PE pregnancies. Human studies remain incomplete, as most approaches have been unable to eliminate neural, humoral, paracrine influences on vessel response. Direct evaluation of the placental arterioles will allow a more direct analysis of vasodilatory responses as related to the endothelial dysfunction in PE. Objective To study placental endothelial function in preeclamptic (PE) and normal placental vessels. Methods To examine the impact of PE on the microvascular function, isolated vessels from placentas of healthy and PE pregnancies were used for videomicroscopy. Endothelial‐dependent dilation to flow (FMD), acetylcholine (ACh) and smooth muscle‐dependent dilation to papaverine were evaluated. Data are presented as a percentage of maximum diameter and were analyzed with 2‐way ANOVA RM with statistical significance set at *p<0.05; data are expressed as mean ± SE. Results Vessels from PE patients resulted in impairment of FMD (control 71.% ±6.6%, PE 31.6%±10.7%*) and dilation to Ach (control 63.6%±9.4, PE 32.7±8.83%*). Smooth muscle‐dependent dilation to papaverine was unchanged between the two groups (Figure ). Conclusion Preliminary studies show impaired endothelial function in placental vessels of subjects with PE, compared to healthy controls, while smooth muscle function was not affected. Understanding the underlying mechanism(s) of vasodilation in placental vasculature will further the understanding the pathophysiology of PE. Support or Funding Information The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, Award NumberUL1TR001436. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the NIH. This project is funded by the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. Vessels from PE patients resulted in impairment of FMD and dilation to ACh. Smooth muscle‐dependent dilation to papaverine was unchanged between the two groups. Statistical significance denoted with *

Vascular Dysfunction in Preeclampsia

“…In terms of molecular targets, less explored areas include the modulation of RGS proteins to mitigate the negative effects of excessive GPCR induction via hormones such as angiotensin II, endothelin-1, and vasopressin [ 213 , 263 ] or the alleviation of cellular stress that leads to mitochondrial dysfunction, cell death, circulating DNA, and subsequent TLR9 activation [ 79 , 83 , 244 , 247 , 252 , 264 , 265 , 266 ]. Though much remains undiscovered, translational research [ 152 , 153 , 154 ], basic animal models [ 155 , 213 , 215 ], and mechanistic cell work [ 56 , 57 , 150 , 213 ] have made a profound impact in the field thus far, and emerging technologies such as trophoblast organoid cultures [ 267 ] provide great potential for new insight. Thus, collaborating across the spectrum, from bench to bedside, will allow the most rapid acceleration in our understanding of preeclampsia and may foster the development of novel targeted therapeutics.…”

“…The endothelium, or inner layer of blood vessels, serves a wide array of functions that encompass but are not constrained to hemostasis, fibrinolysis, regulation of vascular tone, mediation of inflammatory cascades, and permeability [ 146 , 147 , 148 , 149 ]. Endothelial dysfunction, specifically in the form of barrier disruption and impaired vasodilatory capacity, is prevalent in preeclampsia and implicated in many stages of the disease [ 150 , 151 , 152 , 153 , 154 ]. Hemodynamic shifts accompanying compromised endothelial junction integrity, specifically those related to vasopressin, may precede early malfunctions in placental development [ 155 ], or in late-onset preeclampsia, endothelial damage may render a mother unable to buffer trophoblast-derived stress signals that accumulate throughout pregnancy [ 29 , 32 ].…”

“…Preeclamptic plasma restricted endothelium-dependent relaxation, but the effect only occurred with an intact endothelium, demonstrating that the vascular smooth muscle was unimpaired [ 152 ]. Similarly, placental vessels obtained from preeclamptic pregnancies show attenuated endothelial function with unaltered smooth muscle-mediated dilation [ 153 ]. These endothelial-specific findings have also been confirmed in vivo, as endothelium-dependent flow-mediated dilation was impaired in women with a history of preeclampsia compared to those without [ 154 ].…”

“…Additionally, diminished uteroplacental perfusion secondary to elevations in mean arterial pressure is prevented by ETA antagonism in rats [ 207 ]. Both uterine and placental arteries displayed attenuated endothelium-dependent vasodilatory function in the context of preeclampsia [ 152 , 153 ], which may be partially caused by oxidative stress [ 154 , 197 ]. In combination, uteroplacental resistance negatively impacts fetoplacental exchange, while systemic resistance can contribute to glomerular endotheliosis, liver failure, and central nervous system damage.…”