Angiogenic Dysregulation in Pregnancy-Related Hypertension—A Role for Metformin

Abstract

In the face of escalating maternal and fetal health threats, hypertensive pregnancy disorders (HPDs) is one of the leading cause of maternal and fetal morbidity and mortality. The range of HPDs include white-coat hypertension, chronic hypertension, gestational hypertension, mild-to-moderate and severe preeclampsia and eclampsia. Current evidence implicates an imbalance of circulating anti- and angiogenic factors in HPDs emanating from the placental vasculature, impacting on angiogenesis. Delivery of the fetus is thus far the only curative measure, albeit with increased risk. Resultant endothelial dysfunction caused by the excessive production of placental soluble fms-like tyrosine kinase-1 has been the basis of many studies to find a safer treatment strategy. Metformin, used historically in the treatment of diabetes mellitus has also found its therapeutic reach in many other disease states. These include, but are not limited to, improving blood flow in certain cancer types, treatment of polycystic ovarian disease, improving vasodilation, and reducing inflammation. Metformin is used to treat hyperglycemic endothelial dysfunction through the enhancement of the nitric oxide system, endothelin-derived hyperpolarizing factor and sirtuin 1. Similarly, endothelial dysfunction in preeclampsia and other HPDs leads to a hypoxic state and elevated blood pressures. Dubbed as the new "aspirin" of current times, the retardation of the antiangiogenic status by metformin provides an exciting and promising alternate strategy in treating these pregnancy disorders.

Exercise versus Metformin to Improve Pregnancy Outcomes among Overweight Pregnant Women: A Systematic Review and Network Meta-Analysis

“…However, it is difficult to rule out possible benefits of metformin on the risk of preeclampsia considering that metformin has been shown to improve endothelial dysfunction, poor vascularization, hypertension, and preeclampsia-related vasoconstriction by reducing soluble fms-like tyrosine kinase-1 and soluble endoglin levels; in addition, modulation of sirtuin 1 activity improves nitric oxide bioavailability through deacetylation of nitric oxide synthase. Moreover, closing the loop could also improve the activity of complex 1 of the mitochondrial electron transport chain, whose lower activity is associated with endothelial dysfunction [70,71].…”

Current Researches, Rationale, Plausibility, and Evidence Gaps on Metformin for the Management of Hypertensive Disorders of Pregnancy

“…As mentioned in the preeclamptic pathophysiology, imbalanced secretion of angiogenic and antiangiogenic factors from the ischemic placenta results in dysplasia of the placental vessel network, systematic endothelial dysfunction, disturbance of vasomotion, and impaired ability to endothelial repair (Soobryan et al, 2018). Accordingly, PE seems to be not merely a placental disease but also a kind of cardiovascular disease in pregnancy.…”

Prevention of Hypertensive Disorders of Pregnancy—Is There a Place for Metformin?

“…An abnormal invasion of the trophoblast leads to ischemia and hypoxia of the placenta and an increase in the concentrations of circulating vasoactive factors. Antiangiogenic factors such as soluble fms-like tyrosine kinase-1 and soluble endoglin cause imbalances in proand antiangiogenic factors [130]. The possibility of restoring the balance by suppressing antiangiogenic agents seems attractive as a method of effective prophylaxis of preeclampsia.…”