Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure.
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.


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.
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Sribalaji
S
Lakshmikanthan
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Bartosz J
BJ
Zieba
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Zhi-Dong
ZD
Ge
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Ko
K
Momotani
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Xiaodong
X
Zheng
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Hayley
H
Lund
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Mykhaylo V
MV
Artamonov
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Jason E
JE
Maas
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Aniko
A
Szabo
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
David X
DX
Zhang
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
John A
JA
Auchampach
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
David L
DL
Mattson
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee.
Avril V
AV
Somlyo
From the Blood Research Institute, BloodCenter of Wisconsin, Milwaukee (S.L., M.C.W.); Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville (B.J.Z., K.M., M.V.A., A.V.S.); and Department of Pharmacology and Toxicology (Z.-D.G., J.A.A.), Cardiovascular Center (Z.-D.G., X.Z., J.E.M., D.X.Z., J.A.A.), Department of Medicine (X.Z., J.E.M., D.X.Z.), Department of Physiology (H.L., D.L.M.), and Division of Biostatistics (A.S.), Medical College of Wisconsin, Milwaukee. Magdalena.Wodnicka@bcw.edu.
Magdalena
M
Chrzanowska-Wodnicka
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D020668:rap GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C116753:RAP1B protein, human; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins
relaxation; signal transduction; vasodilation