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Influence of physiologic and environmental factors on the role of regulator of G protein signaling 2 (RGS2) in vascular remodeling during pregnancy
Dissertation   Open access

Influence of physiologic and environmental factors on the role of regulator of G protein signaling 2 (RGS2) in vascular remodeling during pregnancy

Jennifer N. Koch
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2020
DOI:
https://doi.org/10.17918/00000261
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Abstract

G proteins--Receptors Preeclampsia Pregnancy--Complications Uterus--Blood-vessels Pharmacology
Decrease in expression or total ablation of regulator of G protein signaling (RGS2) has been implicated in the development of cardiovascular disorders in animal models. Population studies have also shown that mutations in the Rgs2 gene, which are likely associated with decrease in expression or function, are correlated with the development of cardiovascular disorders such as hypertension and pregnancy complications including preeclampsia, especially in overweight subjects. An important function of RGS2 is the regulation of vasocontractile and vasodilatory G protein-coupled receptor (GPCR) signaling cascades in the circulatory system, where it is highly expressed. While the exact etiology of pregnancy complications like preeclampsia remain unknown it is theorized that improper uterine vascular remodeling may be causal as decreased uterine artery blood flow (UABF) leading to insufficient uteroplacental perfusion is associated with these complications. A previous study in our lab found that partial or total loss of RGS2 decreased uterine artery blood flow in a non-pregnant murine model. This discovery along with the knowledge that physiologic factors that likely increase expression of RGS2 are increased during pregnancy led us to postulate that RGS2 may play an important role during pregnancy. Based on the known role of RGS2 and our previous study, we hypothesized that increased expression and function of RGS2 is necessary for proper cardiovascular remodeling to maintain homeostasis and mediates the effects of physiologic and environmental factors on utero-placental perfusion during pregnancy. The studies presented herein determined whether the loss of RGS2 leads to a decrease in UABF during pregnancy. Due to the population studies which associated a mutation in the Rgs2 gene with the development of preeclampsia in overweight women, we also explored whether environmental factors, which lead to increased body mass index (BMI), such as a "Western" style high fat high sucrose (HFHS) diet decrease UABF in conjunction with loss of RGS2. The mRNA expression profile of Rgs2 in the uterine artery was determined during pregnancy by RT-qPCR in order to ascertain the importance of RGS2 in uterine vascular bed at this time. The influence of HFHS diet on the expression profile of Rgs2 during pregnancy was also determined. We found that loss of RGS2 decreased UABF before, during, and after pregnancy, but most significantly at mid-gestation (the period in pregnancy when most complications develop). This was coupled with a significant increase in Rgs2 mRNA expression in the uterine artery at mid-gestation compared to non-pregnant expression levels. This increase in expression at mid-gestation was ablated by feeding the mice a HFHS diet for a period of 4 weeks. We also used ex vivo vessel myography to compare the reactivity of uterine arteries from pregnant WT mice to those of pregnant Rgs2-/- mice in order to uncover the mechanism by which loss of RGS2 decreased UABF. We found that loss of RGS2 increased uterine arterial constriction to phenylephrine, a selective [alpha]1-adrenergic receptor agonist, at mid-gestation. As [alpha]1-adrenergic receptors exclusively couple to the G[alpha]q class G proteins, we therefore concluded that increased expression of RGS2 is necessary in the uterine artery at mid-gestation to regulate contractile G[alpha]q signaling, thereby facilitating increased UABF and adequate uteroplacental perfusion. These studies thus provide evidence for the therapeutic potential of increasing the expression of RGS2 at mid-gestation in order to prevent the development of or treat pregnancy complications, especially in women with decreased expression of RGS2 due to genetic mutations in conjunction with the consumption of an unhealthy diet.

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