Vascular Dysfunction in Preeclampsia

Abstract

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.

Keywords: blood pressure; gestation; hypertension; placenta; preeclampsia; pregnancy; trophoblast; vessel.

Figure 1

Spectrum of hypertensive disorders during pregnancy and their prevalence [9,10,11]. Gestational hypertension is defined by new-onset elevations in blood pressure (<140/90 mmHg) after 20 weeks of gestation, whereas preeclampsia is also accompanied by proteinuria and end-organ dysfunction. Chronic hypertension is present prior to 20 weeks of gestation or continues >12 weeks into the postnatal period and can occur in concert with preeclampsia. Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is classified as a subset of preeclampsia, and eclampsia is a complication of preeclampsia characterized by the addition of seizures.

Figure 2

Identified and proposed mechanisms for abnormal placental development in preeclampsia [49,50,51,52,53,54,55,56,57,58,59] (circHIPK3, circular RNA homeodomain interacting protein kinase 3; LAMA5, laminin subunit alpha-5; VEGFR2, vascular endothelial growth factor receptor 2; pAKT, phosphorylated protein kinase B; pMTOR, phosphorylated mammalian target of rapamycin; TFPI-2, tissue factor pathway inhibitor-2; MAPK, mitogen-activated protein kinase; ERK, extracellular-signal-regulated kinase; MMP, matrix metalloproteinase; HIF-2α, hypoxia-induced factor-2α; ↑ refers to upregulation; ↓ refers to downregulation).

Figure 3

Circulating and placenta-derived vascular substances associated with preeclampsia and their downstream cellular effects [54,101,102,104,105,106,107,114,115,122,123,125,126,130,131,133]. PlGF, VEGFA, and ENG are considered “proangiogenic” factors, whereas sFLT-1 and ENG are “antiangiogenic.” sFLT-1 sequesters PlGF and VEGFA, and sENG blocks TGF-β binding to the ENG receptor (PlGF, placental growth factor; VEGFA, vascular endothelial growth factor A; sFLT-1, soluble fms-like tyrosine kinase 1; ENG, endoglin; sENG, soluble endoglin; VEGFR1 and VEGFR2, vascular endothelial growth factor receptor 1 and 2; TGF-β, transforming growth factor-beta; PLCλ, phospholipase C gamma; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; eNOS, endothelial nitric oxide synthase).

Figure 4

An imbalance in coagulation factors promotes a more prothrombotic environment during preeclampsia [226,227,228]. Prostacyclin is a vasodilatory product of arachidonic acid metabolism derived from endothelial cells [225]. Prostacyclin and aspirin oppose the actions of thromboxane, and the ratio of prostacyclin to thromboxane decreases in preeclampsia [226,229]. The accumulation of placental stress can lead to the release of SDEVs into maternal circulation. SDEVs can promote platelet activation, a precursory step to platelet aggregation and the formation of blood clots [29,230] (SDEV, syncytiotrophoblast-derived extracellular vesicle; VSMC, vascular smooth muscle cell; AA, arachidonic acid).

Figure 5

Maternal factors, including TLR9-induced proinflammatory cytokine release and placental hypoxia, promote a cascade of oxidative stress, mitochondrial DNA damage, cell-free DNA release, TLR9 activation, and subsequent TLR9 activation within the placenta [83,244,245,246,247,248,249,250,251,252,254,255]. Animal and cell culture models indicate that TLR9-related signaling results in decreased angiogenic factors, increased antiangiogenic factors, and impaired trophoblast function [83] (TLR9, toll-like receptor 9; ROS, reactive oxygen species; mtDNA, mitochondrial DNA; cfDNA, cell-free DNA; IFN, interferon; NFκB, nuclear factor kappa B; AP-1, activator protein-1; ↑ refers to upregulation; ↓ refers to downregulation).