Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure. Arterioscler Thromb Vasc Biol 2014 Jul;34(7):1486-94
Date
05/03/2014Pubmed ID
24790136Pubmed Central ID
PMC4224284DOI
10.1161/ATVBAHA.114.303678Scopus ID
2-s2.0-84903159007 (requires institutional sign-in at Scopus site) 40 CitationsAbstract
OBJECTIVE: Small GTPase Ras-related protein 1 (Rap1b) controls several basic cellular phenomena, and its deletion in mice leads to several cardiovascular defects, including impaired adhesion of blood cells and defective angiogenesis. We found that Rap1b(-/-) mice develop cardiac hypertrophy and hypertension. Therefore, we examined the function of Rap1b in regulation of blood pressure.
APPROACH AND RESULTS: Rap1b(-/-) mice developed cardiac hypertrophy and elevated blood pressure, but maintained a normal heart rate. Correcting elevated blood pressure with losartan, an angiotensin II type 1 receptor antagonist, alleviated cardiac hypertrophy in Rap1b(-/-) mice, suggesting a possibility that cardiac hypertrophy develops secondary to hypertension. The indices of renal function and plasma renin activity were normal in Rap1b(-/-) mice. Ex vivo, we examined whether the effect of Rap1b deletion on smooth muscle-mediated vessel contraction and endothelium-dependent vessel dilation, 2 major mechanisms controlling basal vascular tone, was the basis for the hypertension. We found increased contractility on stimulation with a thromboxane analog or angiotensin II or phenylephrine along with increased inhibitory phosphorylation of myosin phosphatase under basal conditions consistent with elevated basal tone and the observed hypertension. Cyclic adenosine monophosphate-dependent relaxation in response to Rap1 activator, Epac, was decreased in vessels from Rap1b(-/-) mice. Defective endothelial release of dilatory nitric oxide in response to elevated blood flow leads to hypertension. We found that nitric oxide-dependent vasodilation was significantly inhibited in Rap1b-deficient vessels.
CONCLUSIONS: This is the first report to indicate that Rap1b in both smooth muscle and endothelium plays a key role in maintaining blood pressure by controlling normal vascular tone.
Author List
Lakshmikanthan S, Zieba BJ, Ge ZD, Momotani K, Zheng X, Lund H, Artamonov MV, Maas JE, Szabo A, Zhang DX, Auchampach JA, Mattson DL, Somlyo AV, Chrzanowska-Wodnicka MAuthors
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMagdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Angiotensin II Type 1 Receptor BlockersAnimals
Antihypertensive Agents
Blood Pressure
Cardiomegaly
Cells, Cultured
Dose-Response Relationship, Drug
Endothelial Cells
Female
Humans
Hypertension
Male
Mice
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Nitric Oxide
Nitric Oxide Synthase Type III
Phosphorylation
RNA Interference
Signal Transduction
Time Factors
Transfection
Vasoconstriction
Vasoconstrictor Agents
Vasodilation
Vasodilator Agents
rap GTP-Binding Proteins
