Regulator of G Protein Signaling 2 Facilitates Uterine Artery Adaptation During Pregnancy in Mice

Abstract

Background: Decreased uterine blood flow is known to contribute to pregnancy complications such as gestational hypertension and preeclampsia. Previously, we showed that the loss of regulator of G protein signaling 2 (RGS2), a GTPase activating protein for Gq/11 and Gi/o class G proteins, decreases uterine blood flow in the nonpregnant state in mice. Here, we examined the effects of the absence of RGS2 and 5 on uterine blood flow and uterine vascular structure and function at early, mid, and late gestation, as well as peripartum period in mice. Methods and Results: Abdominal Doppler ultrasonography was performed on adult female wild-type, Rgs2−/−, and Rgs5−/− mice at pre-pregnancy, gestational days 10, 15, and 18, and postpartum day 3. Uterine artery structure and function were also assessed by vessel myograph studies. At mid-pregnancy, uterine blood flow decreased in both Rgs2−/− and Rgs5−/− mice, whereas resistive index increased only in Rgs2−/− mice. In uterine arteries from wild-type mice, mRNA expression of RGS2 and 4 increased, whereas RGS5 expression remained elevated at mid-pregnancy. These changes in gene expression were unique to uterine arteries because they were absent in mesenteric arteries and the aorta of wild-type mice. In Rgs2−/− mice, uterine artery medial cross-sectional area and G protein–coupled receptor-mediated vasoconstriction increased in mid-pregnancy, implicating a role for RGS2 in structural and functional remodeling of uterine arteries during pregnancy. In contrast, RGS5 absence increased vasoconstriction only in the peripartum period. Conclusions: These data together indicate that RGS2 plays a critical role in the structural and functional remodeling of uterine arteries to impact uterine blood flow during pregnancy. Targeting the signaling pathway regulated by RGS2 may therefore be a therapeutic strategy for ameliorating utero-placental perfusion disorders during pregnancy.