Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Abstract

Preeclampsia is a pregnancy-related disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia.

Markedly higher sFlt‐1/PlGF ratio in a woman with acute fatty liver of pregnancy compared with HELLP syndrome

“…In women with HELLP syndrome, the levels of sFlt‐1 were all less than 100 000 pg/mL. Because the abnormality of sFlt‐1 levels in pregnancy is related to endothelial dysfunction in pre‐eclampsia, the markedly increased levels of sFlt‐1 in our AFLP patient might have reflected severer endothelial dysfunction underlying this condition, and thereby might have been associated with the genesis of liver dysfunction, renal dysfunction, low AT activity and thrombocytopenia, and also associated with the slow amelioration of all these abnormalities.…”

The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study

“…Such parameters have been studied with relatively simple methods, such as hormonal determinations (20,21,27), concentrations of nutrients/fuels (glucose (17)(18)(19), lipids(28-33), proteins(34-40), amino acids(41-43)), blood pressure (8,44), cardiovascular function (9,11), spirometry (13,16), immunological assays (14,24,45), and different tests of central nervous system function (25,26). These studies have been essential to understand changes in body composition (4,18), physiologic adaptation (10,13), pathophysiology of selected pregnancy complications (17,(46)(47)(48). One of the domains of interest that has proven to be extraordinarily successful is the study of changes in plasma protein concentrations in maternal blood.…”

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

“…However, it is commonly agreed upon that the initiating detrimental events occur at the maternal/fetal interface, where invading fetal cytotrophoblasts fail to convert the maternal spiral arteries into high‐capacitance, low‐resistance vessels, leading to occlusive arterial lesions in the myometrial segment of the arteries24, 25 and a reduction in uterine perfusion pressure 20, 26. Unable to meet the metabolic demands of the developing fetus because of this compromised arterial blood supply, the placenta enters a chronically hypoxic/ischemic state,27 which activates pathways that increase the production of inflammatory cytokines,20 reactive oxygen species,28 and angiogenic imbalance factors including the soluble form of the vascular endothelial growth factor (VEGF) receptor Flt‐1 (sFlt‐1),29 all of which lead to systemic endothelial dysfunction that is manifested as hypertension 30. Among these, sFlt‐1 has been implicated as a major driver of the preeclampsia syndrome because of its high levels in the plasma of preeclamptic mothers31 and the fact that exogenously administered sFlt‐1 induces a preeclampsia‐like syndrome in pregnant rodents 32, 33, 34, 35…”