Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia

Abstract

Preeclampsia is a pregnancy-associated disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality; however, the pathophysiological mechanisms involved are unclear. Predisposing demographic, genetic and environmental risk factors could cause localized abnormalities in uteroplacental cytoactive factors such as integrins, matrix metalloproteinases, cytokines and major histocompatibility complex molecules leading to decreased vascular remodeling, uteroplacental vasoconstriction, trophoblast cells apoptosis, and abnormal development of the placenta. Defective placentation and decreased trophoblast invasion of the myometrium cause reduction in uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia, an important event in preeclampsia. RUPP could stimulate the release of circulating bioactive factors such as the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin that cause imbalance with the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or cause the release of inflammatory cytokines, reactive oxygen species, hypoxia-induced factor-1 and AT1 angiotensin receptor agonistic autoantibodies. The circulating bioactive factors target endothelial cells causing generalized endotheliosis, endothelial dysfunction, decreased vasodilators such as nitric oxide and prostacyclin and increased vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction. The bioactive factors also stimulate the mechanisms of VSM contraction including Ca2+, protein kinase C, and Rho-kinase and induce extracellular matrix remodeling leading to further vasoconstriction and hypertension. While therapeutic options are currently limited, understanding the underlying mechanisms could help design new interventions for management of preeclampsia.

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

“…5) Treatment with the angiogenic factor PIGF or Preg placental extract, which we found to contain high PlGF and low sFlt-1 levels, increased MMP-2 and MMP-9 levels/activity in placenta and uterus of RUPP rats. The present observations with PlGF are consistent with our previous report that the angiogenic factor VEGF prevents the decreases in MMP-2 and MMP-9 in uterine, placental and aortic segments of RUPP rats [13], and other reports that PIGF promotes endothelial cell growth, vasculogenesis, and placental development [20]. …”

“…sFlt-1 binds VEGF and PlGF in the circulation and inhibits their action on cell surface VEGFR-1 [34]. Circulating levels of sFlt-1 are 10-fold higher in pregnant than non-pregnant women, remain almost stable during the first and second trimester, then increase after the 36 th week of gestation and throughout the third trimester [20]. The circulating sFlt-1 levels and sFlt-1/PlGF ratio are much higher in preeclamptic than normal pregnant women from the second trimester onwards [25, 29, 33, 35, 36].…”

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

“…In support of this paradigm, studies have shown changes in the local and circulating levels of multiple factors including the pro-angiogenic vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), the anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), hypoxia-inducible factor (HIF), reactive oxygen species (ROS) and angiotensin II (AngII) type 1 receptor (AT 1 R) agonistic autoantibodies (AT 1 -AA). These bioactive factors could in turn cause generalized EC dysfunction and HTN, renal glomerular endotheliosis and increased glomerular permeability leading to proteinuria, and cerebral endotheliosis leading to cerebral edema and seizures (Ali and Khalil, 2015; Shah and Khalil, 2015). …”

Adjunctive Use of Esomeprazole in the Treatment of Pre-Eclampsia: A Case Report and Literature Review

“…The hypoxia provokes the release of ROS, angiogenic and inflammatory cytokines, for example hypoxia-inducible factor-I while decreasing heme oxygenase-I (HO-I) and its metabolite carbon monoxide. [53] Changes in sFLT-I and PIGF precede clinical development of pre-eclampsia only. While changes in sEGN and PIGF precede delivery of small-for-gestational age neonate.…”