Abstracts from the 10th World Congress for Microcirculation

Pregnancy induces extensive adaptation of maternal cardiovascular physiology. Despite increased cardiac output and plasma volume, blood pressure decreases due to reduced peripheral resistance. The renin-angiotensin system is crucial for these adaptations. Paradoxically, healthy pregnant women are resistant to pressor effects of infused angiotensin II (AngII), in contrast to women with preeclampsia. The mechanisms contributing to reduced peripheral resistance of pregnancy remain poorly understood. We hypothesized that AngII signaling could be regulated at a post-receptor level by Regulator of G protein signaling (RGS) molecules; these are intracellular GTPase-activating (GAP) proteins for heterotrimeric G proteins which tightly control GPCR activation including ATR1. Indeed, RGS5 is a major regulator of hemodynamic adaptation during pregnancy. In normal pregnancy, RGS5 levels increase with plasma volume expansion and antagonize AngII signaling. In contrast, loss of RGS5 in pregnant mice increases AngII sensitivity, causing vascular dysfunction and gestational hypertension. Further challenge by increasing AngII levels results in preeclampsialike symptoms, namely, more severe hypertension, proteinuria, placental pathology and reduced birth weight. In humans, RGS5 expression in myometrial arteries is suppressed in hypertensive/preeclamptic pregnancies indicating a similar regulatory role. Importantly, ablation of a single RGS5 allele in mice is sufficient to trigger pregnancy-induced hypertension in previously asymptomatic individuals. Upregulation of RGS5 expression via peroxisome proliferator activated receptor (PPAR) activation normalizes vascular function and blood pressure in pregnant heterozygote null mice. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling, and its modulation is a promising therapeutic strategy for pregnancy-related hypertensio