Regulator of G Protein Signaling 5 Controls Blood Pressure Homeostasis and Vessel Wall Remodeling
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 non-redundant role in the pathogenesis of hypertension and 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 (AngII) infusion. Using a knockout mouse model, radio-telemetry 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 PKC, MEK/ERK 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 (ATR1) and major Gαq-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.
- G protein coupled receptor signaling
- Regulator of G protein signaling
- vessel wall remodeling
- smooth muscle cells
- animal model cardiovascular disease
- arterial stiffness
- blood pressure
- vascular remodeling
- vascular smooth muscle
- Received September 21, 2012.
- Revision received January 7, 2013.
- Accepted January 9, 2013.
- Copyright © 2013, Circulation Research