Published online before print June 12, 2006, doi: 10.1161/CIRCULATIONAHA.106.611822
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2006;113:2818-2825.)
© 2006 American Heart Association, Inc.
Hypertension |
Bone Morphogenic Protein-4 Induces Hypertension in Mice
Role of Noggin, Vascular NADPH Oxidases, and Impaired Vasorelaxation
From the Division of Cardiology (S.M., M.C.G.N., S.D., D.G.H., H.J.), Emory University, and the Wallace H. Coulter Department of Biomedical Engineering (C.M., D.S., H.J.), Georgia Institute of Technology and Emory University, Atlanta, Ga.
Correspondence to Hanjoong Jo, PhD, Wallace H. Coulter Department of Biomedical Engineering at the Institute of Technology and Emory University, 2005 WMBR, Atlanta, GA 30322. E-mail hanjoong.jo{at}bme.gatech.edu
Received January 2, 2006; revision received April 1, 2006; accepted April 14, 2006.
Background— Recent in vitro studies have shown that disturbed flow and oxidative conditions induce the expression of bone morphogenic proteins (BMPs 2 and 4) in cultured endothelial cells. BMPs can stimulate superoxide production and inflammatory responses in endothelial cells, raising the possibility that BMPs may play a role in vascular diseases such as hypertension and atherosclerosis. In this study, we examined the hypothesis that BMP4 would induce hypertension in intact animals by increasing superoxide production from vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and an impairment of vasodilation responses.
Methods and Results— BMP4 infusion by osmotic pumps increased systolic blood pressure in a time- and dose-dependent manner in both C57BL/6 mice (from 101 to 125 mm Hg) and apolipoprotein E–null mice (from 107 to 146 mm Hg) after 4 weeks. Cotreatment with the BMP antagonist noggin or the NADPH oxidase inhibitor apocynin completely blocked the BMP4 effect. In addition, BMP4 infusion stimulated aortic NADPH oxidase activity and impaired vasorelaxation, both of which were prevented either by coinfusing noggin or by treating the isolated aortas with apocynin. BMP4, however, did not cause significant changes in maximum relaxation induced by the endothelium-independent vasodilator nitroglycerin. Remarkably, BMP4 infusion failed to stimulate aortic NADPH oxidases, increase blood pressure, and impair vasodilation responses in p47phox-deficient mice.
Conclusions— These results suggest that BMP4 infusion induces hypertension in mice in a vascular NADPH oxidase–dependent manner and the subsequent endothelial dysfunction. We suggest that BMP4 is a novel mediator of endothelial dysfunction and hypertension and that noggin and its analogs could be used as therapeutic agents for treating vascular diseases.
CLINICAL PERSPECTIVE
This article has been cited by other articles:
 |
|
 |
|
  T. Helbing, F. Volkmar, U. Goebel, J. Heinke, P. Diehl, H. L. Pahl, C. Bode, C. Patterson, and M. Moser Kruppel-like factor 15 regulates BMPER in endothelial cells Cardiovasc Res, October 18, 2009; (2009) cvp314v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Nam, C.-W. Ni, A. Rezvan, J. Suo, K. Budzyn, A. Llanos, D. Harrison, D. Giddens, and H. Jo Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1535 - H1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Maloney, I. R. Sweet, D. M. Hockenbery, M. Pham, N. O. Rizzo, S. Tateya, P. Handa, M. W. Schwartz, and F. Kim Activation of NF-{kappa}B by Palmitate in Endothelial Cells: A Key Role for NADPH Oxidase-Derived Superoxide in Response to TLR4 Activation Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1370 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sucosky, K. Balachandran, A. Elhammali, H. Jo, and A. P. Yoganathan Altered Shear Stress Stimulates Upregulation of Endothelial VCAM-1 and ICAM-1 in a BMP-4- and TGF-{beta}1-Dependent Pathway Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 254 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Csiszar, N. Labinskyy, H. Jo, P. Ballabh, and Z. Ungvari Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H569 - H577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Kline, D. J. Kleinhenz, B. Liang, S. Dikalov, D. M. Guidot, C. M. Hart, D. P. Jones, and R. L. Sutliff Vascular oxidative stress and nitric oxide depletion in HIV-1 transgenic rats are reversed by glutathione restoration Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2792 - H2804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Rhee, P. J. Santangelo, H. Jo, and G. Bao Target accessibility and signal specificity in live-cell detection of BMP-4 mRNA using molecular beacons Nucleic Acids Res., March 1, 2008; 36(5): e30 - e30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Miller, W. C. Watson, K. A. Kerr, C. A. Labarrere, N. X. Chen, M. A. Deeg, and J. L. Unthank Development of progressive aortic vasculopathy in a rat model of aging Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2634 - H2643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. I. Ungvari Endothelium-Derived Bone Morphogenic Protein Antagonists May Counteract the Proatherogenic Vascular Effects of Bone Morphogenic Protein 4 Circulation, September 11, 2007; 116(11): 1221 - 1223. [Full Text] [PDF]
|
|
|
|
|
|
K. Chang, D. Weiss, J. Suo, J. D. Vega, D. Giddens, W. R. Taylor, and H. Jo Bone Morphogenic Protein Antagonists Are Coexpressed With Bone Morphogenic Protein 4 in Endothelial Cells Exposed to Unstable Flow In Vitro in Mouse Aortas and in Human Coronary Arteries: Role of Bone Morphogenic Protein Antagonists in Inflammation and Atherosclerosis Circulation, September 11, 2007; 116(11): 1258 - 1266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Martin, P. Du, A. Dikalova, B. Lassegue, M. Aleman, M. C. Gongora, K. Brown, G. Joseph, D. G. Harrison, W. R. Taylor, et al. Reactive oxygen species-selective regulation of aortic inflammatory gene expression in Type 2 diabetes Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2073 - H2082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Csiszar, N. Labinskyy, K. E. Smith, A. Rivera, E. N.T.P. Bakker, H. Jo, J. Gardner, Z. Orosz, and Z. Ungvari Downregulation of Bone Morphogenetic Protein 4 Expression in Coronary Arterial Endothelial Cells: Role of Shear Stress and the cAMP/Protein Kinase A Pathway Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 776 - 782. [Abstract] [Full Text] [PDF]
|
|