Coordinated activation of VEGFR-1 and VEGFR-2 is a potent arteriogenic stimulus leading to enhancement of regional perfusion

Objective: The process of arteriogenesis is driven by various growth factors including vascular endothelial growth factor (VEGF)-A, which mediates its activity through VEGFR-2 (Flk-1/KDR) on endothelial cells and through VEGFR-1 (Flt-1) on endothelial cells and monocytes. The purpose of this study was to identify which of the VEGF receptors are involved in arteriogenesis in vivo. Methods: Collateral vessel growth was induced by femoral artery ligation in a mouse model of hindlimb ischemia. Following ligation, Balb/c mice were treated with different growth factors (VEGF-A, VEGF-E, PIGF-2, VEGF-E plus PIGF-2 or VEGF-A plus PIGF-2, activating either VEGFR-1, VEGFR-2, or both). After 1 week of treatment, hindlimb perfusion was assessed by perfusion scintigraphy using Tc-99m-MIBI. Results: The strongest improvement of regional perfusion was achieved by simultaneous activation of VEGFR-1 and VEGFR-2, using either VEGF-A or VEGF-A plus PIGF-2, with elevation of relative perfusion in the ischemic limbs from 0.61 to 0.83. The partial restoration in perfusion was associated with morphological changes typical for arteriogenesis. Moreover, specific inhibition of both VEGF-receptors using ZK 202650 resulted in a significant inhibition of arteriogenesis, indicating an active role of the VEGF system in compensatory arteriogenesis. Conclusion: The coordinated activation of both VEGFR-1 and VEGFR-2 represents a more potent arteriogenesic stimulus compared to the isolated activation of either one of these two receptors. These data imply that the activation of both monocytes and endothelial cells is necessary to obtain a maximal VEGF-induced activation of arteriogenesis. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.