Abstract
G-Protein coupled receptors (GPCRs) activate intracellular signalling pathways by coupling to heterotrimeric G-proteins that control many physiological processes including blood pressure homeostasis. The Regulator of G-Protein Signalling-1 (RGS1) controls the magnitude and duration of downstream GPCR signalling by acting as a GTPase-activating protein for specific Gα-proteins. RGS1 has contrasting roles in haematopoietic and non-haematopoietic cells. Rgs1−/−ApoE−/− mice are protected from Angiotensin II (Ang II)-induced aortic aneurysm rupture. Conversely, Ang II treatment increases systolic blood pressure to a greater extent in Rgs1−/−ApoE−/− mice than ApoE−/− mice, independent of its role in myeloid cells. However the precise role of RGS1 in hypertension and vascular-derived cells remains unknown. We determined the effects of Rgs1 deletion on vascular function in ApoE−/− mice. Rgs1 deletion led to enhanced vasoconstriction in aortas and mesenteric arteries from ApoE−/− mice in response to phenylephrine (PE) and U46619 respectively. Rgs1 was shown to have a role in the vasculature, with endothelium-dependent vasodilation being impaired, and endothelium-independent dilatation to SNP being enhanced in Rgs1−/−ApoE−/− mesenteric arteries. To address the downstream signalling pathways in vascular smooth muscle cells (VSMCs) in response to Ang II-stimulation, we assessed pErk1/2, pJNK and pp38 MAPK activation in VSMCs transiently transfected with Rgs1. pErk1/2 signalling but not pJNK and pp38 signalling was impaired in the presence of Rgs1. Furthermore, we demonstrated that the enhanced contractile response to PE in Rgs1−/−ApoE−/− aortas was reduced by a MAPK/Erk (MEK) inhibitor and an L-type voltage gated calcium channel antagonist, suggesting that Erk1/2 signalling and calcium influx are major effectors of Rgs1-mediated vascular contractile responses, respectively. These findings indicate RGS1 is a novel regulator of blood pressure homeostasis and highlight RGS1-controlled signalling pathways in the vasculature that may be new drug development targets for hypertension.
Highlights
Hypertension is a key risk factor for the development of cardiovascular diseases that can be associated with increased G protein-coupled receptor (GPCR) signalling
We have previously shown that Regulator of GProtein Signalling-1 (RGS1) has a critical role in regulating Ang angiotensin II (II) mediated aortic aneurysm rupture in ApoE−/− mice through attenuation of Gαi chemokine receptor signalling in leukocytes [6]
The modulation of blood pressure by GPCRs is essential in the maintenance of normal cardiovascular function, which when compromised can result in vascular dysfunction and hypertension, a risk factor for peripheral atherosclerosis, renal failure, myocardial infarction and stroke
Summary
Hypertension is a key risk factor for the development of cardiovascular diseases that can be associated with increased G protein-coupled receptor (GPCR) signalling. Vasoactive substances that activate GPCRs can regulate blood pressure homeostasis by effecting vessel tone acutely. Longer term changes in systemic pressure and cardiac output leading to vascular dysfunction can result in clinical complications, indicating that tight regulation of GPCR signalling pathways is required to control blood pressure [1]. Many physiologically important vasoactive substances such as angiotensin II (Ang II), noradrenaline, acetylcholine (ACh) signal through multiple GPCRs that couple to the heterotrimeric G-protein families of the Gαq and Gαi subunits [2]. In SMCs, both Ang II and noradrenaline mediate vasoconstriction by activation of Gαq coupled receptors. Signalling by Gαq coupled receptor signalling activates several intracellular pathways including diacylglycerol (DAG) and inositol 1,4,5trisphosphate (IP3), resulting in activation of protein kinase C (PKC)
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