Regulator of G-protein signaling 5 controls blood pressure homeostasis and vessel wall remodeling
| Autor: | Leonard F Arnolda, Douglas J. McKitrick, Livia C. Hool, Ruth Ganss, Vasyl Holobotovskyy, Erin Bolitho, Jennifer Burchell, Marianne Tare, Mitali Manzur, Helena M. Viola |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty Vascular smooth muscle Physiology MAP Kinase Signaling System Blood Pressure Biology Muscle Smooth Vascular Mice Regulator of G protein signaling Internal medicine medicine Animals Homeostasis Protein kinase A Rho-associated protein kinase Protein Kinase C Mice Knockout rho-Associated Kinases medicine.disease Angiotensin II G Protein-Coupled Receptor Signaling Cell biology Disease Models Animal Endocrinology Vasoconstriction Pathophysiology of hypertension Hypertension Blood Vessels Female Signal transduction Cardiology and Cardiovascular Medicine RGS Proteins Signal Transduction |
| Zdroj: | Circulation research. 112(5) |
| ISSN: | 1524-4571 |
| Popis: | Rationale: Regulator of G-protein signaling 5 (RGS5) modulates G-protein-coupled receptor signaling and is prominently expressed in arterial smooth muscle cells. Our group first reported that RGS5 is important in vascular remodeling during tumor angiogenesis. We hypothesized that RGS5 may play an important role in vessel wall remodeling and blood pressure regulation. Objective: To demonstrate that RGS5 has a unique and nonredundant role in the pathogenesis of hypertension and to identify crucial RGS5-regulated signaling pathways. Methods and Results: We observed that arterial RGS5 expression is downregulated with chronically elevated blood pressure after angiotensin II infusion. Using a knockout mouse model, radiotelemetry, and pharmacological inhibition, we subsequently showed that loss of RGS5 results in profound hypertension. RGS5 signaling is linked to the renin–angiotensin system and directly controls vascular resistance, vessel contractility, and remodeling. RGS5 deficiency aggravates pathophysiological features of hypertension, such as medial hypertrophy and fibrosis. Moreover, we demonstrate that protein kinase C, mitogen-activated protein kinase/extracellular signal–regulated kinase, and Rho kinase signaling pathways are major effectors of RGS5-mediated hypertension. Conclusions: Loss of RGS5 results in hypertension. Loss of RGS5 signaling also correlates with hyper-responsiveness to vasoconstrictors and vascular stiffening. This establishes a significant, distinct, and causal role of RGS5 in vascular homeostasis. RGS5 modulates signaling through the angiotensin II receptor 1 and major Gα q -coupled downstream pathways, including Rho kinase. So far, activation of RhoA/Rho kinase has not been associated with RGS molecules. Thus, RGS5 is a crucial regulator of blood pressure homeostasis with significant clinical implications for vascular pathologies, such as hypertension. |
| Databáze: | OpenAIRE |
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