title: Angiotensin II induces capillary formation from endothelial cells via the LOX-1 dependent redox-sensitive pathway.
abstract: 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.
authors: Department of Internal Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205-7199, USA.
authors: Changping
authors: C
authors: Hu
authors: Abhijit
authors: A
authors: Dandapat
authors: Jawahar L
authors: JL
authors: Mehta
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D002196:Capillaries / Q000166:cytology* / Q000254:growth & development; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; C495138:Olr1 protein, mouse; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; C073402:PD 123319; D048051:p38 Mitogen-Activated Protein Kinases