title: The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension.
abstract: Although hypertension is a worldwide health issue, an incomplete understanding of its aetiology has hindered our ability to treat this complex disease. Here we identify arhgap42 (also known as GRAF3) as a Rho-specific GAP expressed specifically in smooth muscle cells (SMCs) in mice and humans. We show that GRAF3-deficient mice exhibit significant hypertension and increased pressor responses to angiotensin II and endothelin-1; these effects are prevented by treatment with the Rho-kinase inhibitor, Y27632. RhoA activity and myosin light chain phosphorylation are elevated in GRAF3-depleted SMCs in vitro and in vivo, and isolated vessel segments from GRAF3-deficient mice show increased contractility. Taken together, our data indicate that GRAF3-mediated inhibition of RhoA activity in vascular SMCs is necessary for maintaining normal blood pressure homoeostasis. Moreover, these findings provide a potential mechanism for a hypertensive locus recently identified within arhgap42 and provide a foundation for the future development of innovative hypertension therapies.
authors: Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA.
authors: Xue
authors: X
authors: Bai
authors: Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA.
authors: Kaitlin C
authors: KC
authors: Lenhart
authors: Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA.
authors: Kim E
authors: KE
authors: Bird
authors: Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA.
authors: Alisa A
authors: AA
authors: Suen
authors: McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Mauricio
authors: M
authors: Rojas
authors: Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA.
authors: Masao
authors: M
authors: Kakoki
authors: Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA.
authors: Feng
authors: F
authors: Li
authors: 1] Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA [2] McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Oliver
authors: O
authors: Smithies
authors: 1] Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA [2] McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Christopher P
authors: CP
authors: Mack
authors: 1] Department of Pathology and Lab Medicine, University of North Carolina, 501 Brinkhous-Bullitt Building CB 7525, Chapel Hill, North Carolina 27599, USA [2] McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Joan M
authors: JM
authors: Taylor
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics; D001808:Blood Vessels / Q000503:physiopathology; D002478:Cells, Cultured; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000804:Angiotensin II; D020690:GTPase-Activating Proteins; D018994:Myosin Light Chains; D020742:rhoA GTP-Binding Protein; C000589233:Arhgap42 protein, Mouse; C000589232:ARHGAP42 protein, human