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, w...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-05, Vol.105 (18), p.6702-6707
Main Authors: Michael, Simon K, Surks, Howard K, Wang, Yuepeng, Zhu, Yan, Blanton, Robert, Jamnongjit, Michelle, Aronovitz, Mark, Baur, Wendy, Ohtani, Kenichi, Wilkerson, Michael K, Bonev, Adrian D, Nelson, Mark T, Karas, Richard H, Mendelsohn, Michael E
Format: Article
Language:English
Subjects:
Aldosterone - blood
Animals
Arteries
Biological Sciences
Blood pressure
Cells
Cyclic GMP-Dependent Protein Kinase Type I
Cyclic GMP-Dependent Protein Kinases - metabolism
Diet
Gene expression regulation
Heart
Hypertension
Hypertension - enzymology
Hypertension - physiopathology
Kidneys
Mice
Muscle, Smooth, Vascular - enzymology
Muscle, Smooth, Vascular - physiopathology
Oxides
Phosphatases
rhoA GTP-Binding Protein - metabolism
Risk factors
Rodents
Smooth muscle
Stress fibers
Studies
Vascular Resistance
Vasomotor System - enzymology
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Summary: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 PKGIα 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 PKGIα mutant mice are normal. These data reveal that PKGIα 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0802128105