VEGF contributes to hypoxic vascular remodeling of ovine carotid arteries

Hypoxic increases in VEGF are pro-angiogenic but also may exert important trophic effects on non-endothelial tissues. To test this hypothesis, endothelium-denuded common carotid arteries from term fetal and non-pregnant adult sheep maintained at sea level (FN, AN) or after 110 days at 3820 m (FH, AH) were used to determine active (high K+) stress-strain relations before organ culture, after 48h of serum starvation, or after 24h starvation + 24h treatment with low physiological concentration (3 ng/ml) of VEGF. Chronic hypoxia increased wall thickness (F: 15%, A: 23%), wall stiffness (F: 13%; A: 24%), smooth muscle alpha actin expression (F: 7%; A: 47%), and regulatory myosin light chain (RLC) expression (F: 89%, A: 82%) and also significantly depressed myogenic tone (F: 74%; A: 40%) and myosin light chain kinase expression (F: 99%; A: 97%). Organ culture with VEGF increased actin expression up to 15% (AH), RLC expression up to 15% (FN & FH) and MLCK up to 133% (FN); all VEGF effects were highly age-dependent. Importantly, all effects of both hypoxia and VEGF varied significantly among different smooth muscle layers as a function of relative position between the lumen and adventitia, supporting a gradient effect. Together, the results support the hypothesis that VEGF participates in age-dependent hypoxic vascular remodeling through direct effects on vascular smooth muscle. Supported by PHS grant# PO1-HD31226