Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries

Abstract

Studies suggest that arteriolar pressure-induced vasoconstriction can be initiated by G protein-coupled receptors, including the angiotensin II type 1 receptor (AT1R). This raises the question, are such mechanisms regulated by negative feedback? The present studies examined whether regulators of G-protein signaling proteins (RGS) in vascular smooth muscle cells (VSMCs) are co-localized with the AT1R when activated by mechanical stress or angiotensin II (Ang II) and if this modulates AT1R-mediated vasoconstriction. To determine if activation of the AT1R recruits RGS5, an in situ proximity ligation assay (PLA) was performed in primary cultures of cremaster muscle arteriolar VSMCs treated with Ang II or hypotonic solution in the absence or presence of candesartan (an AT1R blocker). PLA results revealed a concentration-dependent increase in trafficking/translocation of RGS5 towards the activated AT1R, which was attenuated by candesartan. In intact arterioles, knockdown of RGS5 enhanced constriction to Ang II and augmented myogenic responses to increased intraluminal pressure. Myogenic constriction was attenuated to a higher degree by candesartan in RGS5 siRNA-transfected arterioles, consistent with RGS5 contributing to down regulation of AT1R-mediated signaling. Further, translocation of RGS5 was impaired in VSMCs of spontaneously hypertensive rats (SHR). This is consistent with dysregulated (RGS5-mediated) AT1R signaling that could contribute to excessive vasoconstriction in hypertension. In intact vessels, candesartan reduced myogenic vasoconstriction to a greater extent in SHR compared to controls. Collectively, these findings suggest that AT1R activation results in translocation of RGS5 towards the plasma membrane, limiting AT1R-mediated vasoconstriction through its role in Gq/11 protein-dependent signaling.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Both AT 1A R and AT 1B R appear mechanosensitive (81, 928). RGS5 appears to inhibit mechano-activated AT 1 R in VSMCs (390). For a comprehensive layout of basic ANG II/AT 1 R signaling mechanisms, please see…”

Human cytomegalovirus promoting endothelial cell proliferation by targeting regulator of G-protein signaling 5 hypermethylation and downregulation

“…Additionally, the expression level of RGS5 in the vascular smooth muscle and intima was markedly reduced in spontaneously hypertensive rats and adrenocorticotropic hormone-and Ang-II-induced hypertensive rats, while the blood pressure level was increased in RGS5-knockout mice 37,40,41 . Moreover, RGS5 might also be involved in the regulation of blood pressure by modulating Na + transport in renal epithelial cells, G renal epit AngII type 1 receptor signaling, protein kinase C, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), RhoA kinase activation-mediated increases in vascular resistance and vascular remodeling, and downregulation of peroxisome proliferator-activated receptor β-induced oxidative stress and inflammatory responses 37,[42][43][44] . However, it is still elusive whether RGS5 can induce dysfunction of ECs in the context of HCMV infection.…”

“…Animal experiments have confirmed that mRNA levels of RGS5 decrease in vascular SMCs in atherosclerotic lesions 58 , and loss of RGS5 results in profound hypertension 37 . Downregulation of RGS5 has been identified in bypass graft neo-intima, atherosclerotic arteries, and hypertension 42,59,60 . Consistent with these findings, we found that RGS5 overexpression reversed the proliferation of ECs induced by HCMV infection, whereas did not influence the effects of HG or ox-LDL on proliferation of ECs.…”

The dopamine receptor D5gene shows signs of independent erosion in Toothed and Baleen whales

“…Thus, in Cetacea, DRD 5 loss could contribute for the peripheral vasoconstriction requirements of diving. Also, by shifting renal salt balance, DRD 5 could also play a role in the maintenance of an adequate blood volume and pressure [15–17,37].…”

“…This hypertensive phenotype appears to result from a central nervous system defect, leading to an increase in sympathetic tone and, consequently, vasoconstriction [2]. Besides neuronal impairment, DRD 5 disruption was also suggested to counter-regulate and modulate the expression of the prohypertensive Angiotensin II Type 1 Receptor (AT 1 R), involved in renal salt balance, blood pressure and vasoconstriction [15–17].…”