The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension

Xue Bai, Kaitlin C. Lenhart, Kim E. Bird, Alisa A. Suen, Mauricio Rojas, Masao Kakoki, Feng Li, Oliver Smithies, Christopher P. Mack and Joan M. Taylor ()
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Xue Bai: University of North Carolina
Kaitlin C. Lenhart: University of North Carolina
Kim E. Bird: University of North Carolina
Alisa A. Suen: University of North Carolina
Mauricio Rojas: McAllister Heart Institute, University of North Carolina
Masao Kakoki: University of North Carolina
Feng Li: University of North Carolina
Oliver Smithies: University of North Carolina
Christopher P. Mack: University of North Carolina
Joan M. Taylor: University of North Carolina

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3910

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