Neuropilin-1 is essential for enhanced VEGF165-mediated vasodilatation in collateral-dependent coronary arterioles of exercise-trained pigs

Abstract

Background/Aims: Exercise training enhances vasodilatation to vascular endothelial growth factor (VEGF165) in collateral-dependent coronary arterioles. Interaction of VEGF receptor 2 (VEGFR-2) and the non-tyrosine-kinase receptor, neuropilin-1 has been reported to potentiate VEGF165- mediated signaling. In the current study, we tested the hypotheses that neuropilin-1 mediates the exercise-enhanced VEGF165-mediated vasodilatation in collateral-dependent arterioles and that neuropilin-1 and/or VEGFR-2 protein levels are increased in these arterioles. Methods: Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of miniature swine. Eight weeks after surgery, the animals were randomized into sedentary or exercise training (treadmill run; 5 days/week; 14 weeks) protocols. Coronary arterioles (∼100 μm diameter) were isolated from both collateral-dependent and control (left anterior descending) myocardial regions and studied by in vitro videomicroscopy or frozen for immunoblot analysis. Results: Exercise-enhanced VEGF165-mediated vasodilatation in collateral-dependent arterioles was reversed by inhibition of the VEGF 165-neuropilin-1 interaction. VEGF121, which does not interact with neuropilin-1, induced similar vasodilatation in arterioles from all treatment groups. Immunoblot revealed significantly elevated VEGFR-1, VEGFR-2 and neuropilin-1 protein levels in collateral-dependent arterioles of exercise-trained pigs. Conclusions: Neuropilin-1 plays a vital role in the exercise-enhanced VEGF165-mediated vasodilatation of collateral-dependent coronary arterioles and is associated with increased neuropilin-1 receptor protein levels. Copyright © 2008 S. Karger AG.