Rgs5 Targeting Leads to Chronic Low Blood Pressure and a Lean Body Habitus

From the B-cell Molecular Immunology section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1876; Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1876; College of Pharmacy, Chungbuk National University, Cheongju, Korea

^* To whom correspondence should be addressed. Email: hcho{at}niaid.nih.gov. jkehrl{at}niaid.nih.gov.

	Abstract

RGS5 is a potent GTPase activating protein for G_i and G_q, which is expressed strongly in pericytes and present in vascular smooth muscle cells. To study the role of RGS5 in blood vessel physiology we generated Rgs5 deficient mice. The Rgs5-/- mice developed normally without obvious defects in cardiovascular development or function. Surprisingly, Rgs5^-/- mice had persistently low blood pressure, greater in female than male mice without concomitant cardiac dysfunction, and a lean body habitus. Examination of the major blood vessels revealed that the aortas from Rgs5^-/- mice are dilated compared to that of control mice without altered wall thickness. Isolated aortic smooth muscle cells from the Rgs5^-/- mice exhibited an exaggerated phosphorylation of vasodilator-stimulated phosphoprotein and ERK in response to stimulation with either sodium nitroprusside or sphingosine-1-phosphate. This study along with previous studies demonstrating that the RGS5 stability is under the control of nitric oxide via the N-end rule pathway suggest that RGS5 may balance vascular tone by attenuating vasodilatory signaling in vivo in opposition to RGS2, another RGS family member known to inhibit GPCR-mediated vasoconstrictor signaling. Blocking the function or expression of RGS5 may provide an alternative approach to treat hypertension.