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 ( RGS 2), a GTP ase activating protein for G q/11 and G i/o class G proteins, decreases uterine blood flow in the nonpregnant state in mice. Here, we examined the effects of the absence of RGS 2 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 RGS 2 and 4 increased, whereas RGS 5 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 RGS 2 in structural and functional remodeling of uterine arteries during pregnancy. In contrast, RGS 5 absence increased vasoconstriction only in the peripartum period. Conclusions These data together indicate that RGS 2 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 RGS 2 may therefore be a therapeutic strategy for ameliorating utero‐placental perfusion disorders during pregnancy.

Vascular Dysfunction in Preeclampsia

“…Regarding the maternal vasculature and complementing this work, Koch et al found that elimination of Rgs2 in mice attenuated uterine artery blood flow and increased the resistive index during mid-gestation [ 215 ]. Hence, these studies indicate that preeclampsia may also be a result of disinhibition of GPCR signaling to various hormones, which contribute to placental and vascular dysfunction [ 213 , 215 ].…”

“…Further, transcriptomic analyses revealed that there was overlap in molecular pathways enriched in human preeclamptic placenta and mice with disrupted Rgs2, including those related to mitochondrial dysfunction, the unfolded protein response, and oxidative stress [213]. Regarding the maternal vasculature and complementing this work, Koch et al found that elimination of Rgs2 in mice attenuated uterine artery blood flow and increased the resistive index during mid-gestation [215]. Hence, these studies indicate that preeclampsia may also be a result of disinhibition of GPCR signaling to various hormones, which contribute to placental and vascular dysfunction [213,215].…”

“…In terms of molecular targets, less explored areas include the modulation of RGS proteins to mitigate the negative effects of excessive GPCR induction via hormones such as angiotensin II, endothelin-1, and vasopressin [ 213 , 263 ] or the alleviation of cellular stress that leads to mitochondrial dysfunction, cell death, circulating DNA, and subsequent TLR9 activation [ 79 , 83 , 244 , 247 , 252 , 264 , 265 , 266 ]. Though much remains undiscovered, translational research [ 152 , 153 , 154 ], basic animal models [ 155 , 213 , 215 ], and mechanistic cell work [ 56 , 57 , 150 , 213 ] have made a profound impact in the field thus far, and emerging technologies such as trophoblast organoid cultures [ 267 ] provide great potential for new insight. Thus, collaborating across the spectrum, from bench to bedside, will allow the most rapid acceleration in our understanding of preeclampsia and may foster the development of novel targeted therapeutics.…”

“…Regulator of G protein signaling (RGS) proteins dampen the strength and duration of GPCR activation by hydrolyzing the guanosine-5′-triphosphate bound to an active Gα subunit [ 211 , 212 , 213 , 214 ]. Of the large family of RGS proteins, RGS2 is of particular importance in buffering this GPCR signaling associated with preeclampsia [ 213 , 215 ] and is present in vascular cells, including endothelial cells [ 216 ], as well as many other cell types of the placenta, including trophoblasts, immune cells, and fibroblasts [ 213 , 217 ]. Recently, Perschbacher et al found that RGS2 was decreased in the placenta during human preeclampsia, and heterozygous knockout in only the fetoplacental unit of mice was sufficient to cause key hallmarks of the disorder, such as diastolic hypertension and proteinuria [ 213 ].…”

“…Overall, the pathogenic vascular state of preeclampsia can be attributed to the decreased synthesis of relaxing substances and elevated vasoconstrictive signaling [ 218 , 219 ]. This signaling may be a consequence of increased abundance or sensitivity to vasoconstrictive hormones as well as disinhibition of these pathways [ 213 , 215 , 218 , 219 ]. Vascular resistance has profound effects, both systemically and on specific vascular beds, and has been demonstrated experimentally in vivo, ex vivo, and in vitro [ 152 , 154 , 197 , 205 , 207 ].…”