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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2435.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Small Concentrations of oxLDL Induce Capillary Tube Formation From Endothelial Cells via LOX-1–Dependent Redox-Sensitive Pathway

Abhijit Dandapat; Changping Hu; Liuqin Sun; Jawahar L. Mehta

From the Department of Cardiovascular Medicine (A.D., C.H., L.S., J.L.M.), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Ark; the Department of Pharmacology (C.H.), School of Pharmaceutical Sciences, Central South University, Changsha, China; and the Department of Ophthalmology (L.S.), Heping Hospital, Changzhi Medical College, Changzhi, China.

Correspondence to J.L. Mehta, MD, PhD, 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

Objective— Vascular endothelial growth factor (VEGF), a key angiogenic growth factor, stimulates angiogenesis. Low levels of reactive oxygen species (ROS) function as signaling molecules for angiogenesis. We postulated that low concentrations of oxLDL might induce low levels of ROS and initiate angiogenesis.

Methods and Results— An in vitro model of tube formation from human coronary artery endothelial cells (HCAECs) was used. oxLDL (0.1, 1, 2, 5 µg/mL) induced VEGF expression and enhanced tube formation. oxLDL-mediated VEGF expression and tube formation were suppressed by a specific blocking anti–LOX-1 antibody. Anti–LOX-1 antibody also reduced oxLDL-induced increase in the expression of NADPH oxidase (gp91^phox and p47^phox subunits) and subsequent intracellular ROS generation, phosphorylation of p38 as well as p44/42MAPK, and NF-B p65 expression. gp91^phox siRNA had a similar effect. The expression of VEGF and NF-B p65 induced by oxLDL was also inhibited by the specific extracellular signal-regulated kinase (ERK) 1/2 inhibitor U0126 and the p38 MAPK inhibitor SB203580. Importantly, the NADPH oxidase inhibitor apocynin, gp91^phox siRNA, U0126, and SB203580 all reduced tube formation in response to oxLDL.

Conclusions— These findings suggest that small concentrations of oxLDL promote capillary tube formation by inducing the expression of VEGF via LOX-1-mediated activation of NADPH oxidase- MAPKs-NF-B pathway.

Low levels of reactive oxygen species function as signaling molecules for angiogenesis. In keeping with this concept, we postulated and found that oxLDL (0.1 to 5 µg/mL) promoted capillary tube formation by inducing the expression of VEGF via LOX-1-mediated activation of NADPH oxidase-MAPKs-NF-B pathway.

Key Words: LOX-1 • oxLDL • angiogenesis • NADPH oxidase • VEGF

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