High blood pressure arising from a defect in vascular function.
Hypertension, a major cardiovascular risk factor and cause of mortality worldwide, is thought to arise from primary renal abnormalities. However, the etiology of most cases of hypertension remains unexplained. Vascular tone, an important determinant of blood pressure, is regulated by nitric oxide, which causes vascular relaxation by increasing intracellular cGMP and activating cGMP-dependent protein kinase I (PKGI). Here we show that mice with a selective mutation in the N-terminal protein interaction domain of PKGIalpha display inherited vascular smooth muscle cell abnormalities of contraction, abnormal relaxation of large and resistance blood vessels, and increased systemic blood pressure. Renal function studies and responses to changes in dietary sodium in the PKGIalpha mutant mice are normal. These data reveal that PKGIalpha is required for normal VSMC physiology and support the idea that high blood pressure can arise from a primary abnormality of vascular smooth muscle cell contractile regulation, suggesting a new approach to the diagnosis and therapy of hypertension and cardiovascular diseases.
Michael
Simon K
SK
Molecular Cardiology Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
Surks
Howard K
HK
Wang
Yuepeng
Y
Zhu
Yan
Y
Blanton
Robert
R
Jamnongjit
Michelle
M
Aronovitz
Mark
M
Baur
Wendy
W
Ohtani
Kenichi
K
Wilkerson
Michael K
MK
Bonev
Adrian D
AD
Nelson
Mark T
MT
Karas
Richard H
RH
Mendelsohn
Michael E
ME
D000450:Aldosterone / Q000097:blood; D000818:Animals; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004032:Diet; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology*; D014655:Vascular Resistance; D014666:Vasomotor System / Q000201:enzymology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000450:Aldosterone; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D020742:rhoA GTP-Binding Protein