Published online before print September 24, 2007, doi: 10.1161/HYPERTENSIONAHA.107.096446
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(Hypertension. 2007;50:952.)
© 2007 American Heart Association, Inc.
Original Articles |
Angiotensin II Induces Capillary Formation From Endothelial Cells Via the LOX-1–Dependent Redox-Sensitive Pathway
From the Department of Internal Medicine and Physiology and Biophysics (C.H., A.D., J.L.M.), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock; and the Department of Pharmacology (C.H.), School of Pharmaceutical Sciences, Central South University, Changsha, China.
Correspondence to Jawahar L. Mehta, Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St, Slot 532, Little Rock, AR 72205-7199. E-mail MehtaJL{at}uams.edu
Angiotensin II (Ang II) induces angiogenesis by stimulating reactive oxygen species–dependent vascular endothelial growth factor (VEGF) expression. Ang II via type 1 receptor upregulates the expression of LOX-1, a lectin-like receptor for oxidized low-density lipoprotein. LOX-1 activation, in turn, upregulates Ang II type 1 receptor expression. We postulated that interruption of the feedback loop between Ang II and LOX-1 might attenuate Ang II–induced VEGF expression and capillary formation. In vitro experiments showed that Ang II (1 nmol/L) induced the expression of LOX-1 and VEGF and enhanced capillary formation from human coronary endothelial cells in Matrigel assay. Ang II–mediated expression of LOX-1 and VEGF, capillary formation, intracellular reactive oxygen species generation, and phosphorylation of p38 as well as p44/42 mitogen-activated protein kinases, were suppressed by anti–LOX-1 antibody, nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin and the Ang II type 1 receptor blocker losartan, but not by the Ang II type 2 receptor blocker PD123319. Expression of VEGF and capillary formation induced by Ang II were also inhibited by the p44/42 mitogen-activated protein kinase inhibitor U0126 and the p38 mitogen-activated protein kinase inhibitor SB203580. In ex vivo experiments, Ang II stimulated capillary sprouting from aortic rings from wild-type mice, and this phenomenon was significantly attenuated by pretreatment of aortic rings with anti–LOX-1 antibody, apocynin, and losartan, but not by PD123319. Importantly, Ang II–induced capillary sprouting was minimal from aortic rings from LOX-1 null mice compared with wild-type mice. These findings suggest that small concentrations of Ang II promote capillary formation by inducing the expression of VEGF via Ang II type 1 receptor/LOX-1–mediated stimulation of the reactive oxygen species-mitogen-activated protein kinase pathway.
Key Words: angiogenesis • angiotensin • LOX-1 • reactive oxygen species • signaling • vascular endothelial growth factor
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