Regulators of G protein signaling in cardiovascular function during pregnancy

Abstract

G protein-coupled receptor signaling mechanisms are implicated in many aspects of cardiovascular control, and dysfunction of such signaling mechanisms is commonly associated with disease states. Investigators have identified a large number of regulator of G protein signaling (RGS) proteins that variously contribute to the modulation of intracellular second-messenger signaling kinetics. These many RGS proteins each interact with a specific set of second-messenger cascades and receptor types and exhibit tissue-specific expression patterns. Increasing evidence supports the contribution of RGS proteins, or their loss, in the pathogenesis of cardiovascular dysfunctions. This review summarizes the current understanding of the functional contributions of RGS proteins, particularly within the B/R4 family, in cardiovascular disorders of pregnancy including gestational hypertension, uterine artery dysfunction, and preeclampsia.

Keywords: B/R4 family; RGS2; RGS5; pregnancy; regulator of G protein signaling.

Fig. 1.

Canonical function of regulator of G protein signaling (RGS) proteins. RGS proteins function to accelerate hydrolysis of GTP bound to the G_α subunit, thereby promoting reassembly of the G_α and G_βγ heterotrimer, and termination of second-messenger signaling. GPCR, G protein-coupled receptor.

Fig. 2.

Expression of mRNA for various RGS family members in placenta and immune cells during human pregnancy. In silico reanalysis of published processed data sets GSE9984 (108), GSE93839 (53), and GSE31976 (161) reveals differential expression of the various RGS family members in whole-thickness human placenta across gestation (A), in different layers of term human placenta (B), and in subsets of human CD4⁺ T cells from nonpregnant women, and maternal and cord blood samples at term (C). While many genes were either not detected or reported in circulating CD4⁺ cells in the GSE31976 data set, the concordance of relative expression levels of individual genes tested, across cell types, is notable.

Fig. 3.

Predicted regulators of RGS2 mRNA. A: transcription factor binding sites between −5 kb and +1 kb of the human RGS2 gene transcription start site (TSS), predicted using the MotifMap software (35), with false discovery rate (FDR) < 0.05. B: microRNA binding sites within the 681 base pair 3′-untranslated region (UTR) of the human RGS2 mRNA transcript, predicted using the TargetScan 7.1 software (3).