Kumar Lab

Pregnancy Vascular Adaptations

When a woman gets pregnant, many changes occur in her body’s systems, and perhaps the most significant and striking change occurs in the cardiovascular system—blood volume increases by 50%, heartbeat increases by 15 beats per minute, cardiac output increases by 30 to 50%, and blood pressure decreases by 10 to 15 mmHg. The most profound changes occur in the uterine artery, as the blood flow increases from 20 ml/min in the nonpregnant state to 800 ml/min in term pregnancy. These pregnancy-related cardiovascular changes are essential to supporting the metabolic and nutritional demands of the developing fetus. Enhanced vasodilation and optimal angiogenesis at the maternal-fetal interface are critical in promoting these cardiovascular adaptations. If optimal vasodilation and angiogenesis fail to occur, pregnancy complications such as gestational hypertension, preeclampsia, and fetal growth restriction manifest.

What mechanisms facilitate pregnancy-related vasodilation and angiogenesis and why these fail to occur in pregnant women with preeclampsia and fetal growth restriction are unclear. Our lab focuses on the role of the angiotensin type 2 receptor (AT2R) and hydrogen sulfide (H2S) in mediating normal pregnancy-related vasodilation and angiogenesis. In addition, we examine what pathophysiological mechanisms prevent vasodilation and angiogenesis in pregnant women with preeclampsia and fetal growth restriction.

Normal maternal vascular adaptations

 AT2R: We have found that pregnancy selectively upregulates uterine arterial endothelial AT2R via differential binding of the ligand-activated estrogen receptor ERβ to a functional estrogen response element within the AT2R promoter. During pregnancy, vasculature undergoes tremendous adaptations to decrease blood pressure and increase uteroplacental perfusion. The mechanisms that contribute to these normal pregnancy vascular adaptations, and the reasons for their failure, leading to preeclampsia, are unclear. In the last six years, we have shown that angiotensin type 2 receptors (AT2R) play an important role in pregnancy-related vascular adaptations. We have shown that (1) pregnancy progressively increases plasma angiotensin II levels with a proportional increase in endothelial vasodilatory AT2R expression and no change in vasoconstrictive AT1R expression. This increased AT2R expression mediates enhanced vasodilation and uterine blood flow, (2) estradiol stimulates uterine artery AT2R expression via ERβ-dependent transcription in a pregnancy-specific endothelium-dependent manner, (3) AT2R expression is downregulated in placental vessels from preeclamptic pregnant women and in animal models of preeclampsia — regarding which, we tested the effectiveness of a novel oral active nonpeptide AT2R agonist (Compound 21/ C21, Vicore Pharma, Sweden) in combating preeclampsia, (4) AT2R activation with C21 promotes in vitro angiogenesis in human uterine artery endothelial cells in a pregnancy-specific manner through the JNK-mediated pathway with associated transcriptional upregulation of multiple proangiogenic proteins, (5) C21 upregulates AT2R expression in preeclamptic placental vessels and improves endothelial nitric oxide production, and C21 treatment in animal models of preeclampsia reverses vascular dysfunction and enhances uterine blood flow and fetal growth. In future research, we plan to examine whether or not AT2R activation can prevent in-utero programmed hypertension in adult offspring, and conduct preclinical toxicological studies.

H2S – H2S is a relatively new but highly potent vasodilator. Whether the H2S system contributes to the 20-to-80-fold rise in uterine blood flow in pregnancy is unknown. We found that pregnancy stimulates an increase in the expression of H2S-synthesizing enzymes, specifically in the uterine artery but not the aorta of pregnant rats. Using transcutaneous micro-ultrasound, we found that inhibiting endogenous H2S production attenuates the pregnancy-associated rise in uterine arterial blood in pregnant rats. Also, wire myography studies show that H2S induced greater vasodilation in pregnant than nonpregnant uterine arteries. These data suggest that H2S plays an essential role in the augmented vasodilation of uterine arteries during pregnancy. Further studies are underway to shed light on H2S-induced signaling mechanisms and to examine their ability to reverse preeclamptic vascular dysfunction.