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Cardiovascular Research 2005 65(3):665-673; doi:10.1016/j.cardiores.2004.08.006
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Copyright © 2004, European Society of Cardiology

Vitamins C and E prevent endothelial VEGF and VEGFR-2 overexpression induced by porcine hypercholesterolemic LDL

José A. Rodríguez*, Beatriz Nespereira, Maitane Pérez-Ilzarbe, Ezequiel Eguinoa and José A. Páramo

Atherosclerosis Research Laboratory, Division of Cardiovascular Pathophysiology, School of Medicine, Foundation for Applied Medical Research, University of Navarra, C/Irunlarrea 1, CIFA, Pamplona Navarra E-31008, Spain

* Corresponding author. Tel.: +34 948 425600x6390; fax: +34 948 425652. Email address: josean{at}unav.es

Objective: Vascular endothelial growth factor (VEGF) is believed to play a role in the development of atherosclerosis and has been found to be increased in hypercholesterolemia. We examined the hypothesis that endothelial VEGF and VEGF receptor-2 (VEGFR-2) expression is upregulated by hypercholesterolemic low-density lipoprotein (LDL) and, because it could be driven by oxidative stress, we tested whether vitamin C and E supplementation could modulate it.

Methods: Native LDL were characterized after isolation from adult normal (C-LDL), hypercholesterolemic (HC-LDL) and hypercholesterolemic mini-pigs receiving vitamins C and E (HCV-LDL). VEGF, VEGFR-2, HIF-1{alpha} and superoxide anion (O2–) productions were measured in porcine coronary endothelial cells (ECs) incubated for 48 h with native LDL. The effect of exogenous ascorbic acid and {alpha}- or β-tocopherol was also studied.

Results: HC-LDL, with high cholesterol (P<0.05) and reduced tocopherol/cholesterol ratio (P<0.05), increased significantly VEGF and VEGFR-2 (p<0.001) in EC, associated with higher O2– and HIF-1{alpha} expression, in comparison with C-LDL and HCV-LDL. The addition of vitamin C and {alpha}- or β-tocopherol to the culture medium prevented the induction of VEGF and VEGFR-2 expression by HC-LDL, both at mRNA and protein levels.

Conclusions: Our data suggest HC-LDL induce endothelial VEGF and VEGFR-2 overexpression at least by increasing oxidative stress, and HIF-1{alpha} is one of the signaling mechanisms involved. Prevention of VEGF and VEGFR-2 upregulation could help explain the beneficial effects of vitamins C and E in hypercholesterolemia-induced experimental atherosclerosis.

KEYWORDS Atherosclerosis; Endothelial factors; Endothelial receptors; Growth factors; Lipoproteins

Time for primary review 31 days


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