© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Coordinated activation of VEGFR-1 and VEGFR-2 is a potent arteriogenic stimulus leading to enhancement of regional perfusion
aDepartment of Internal Medicine II, Ulm University Medical Center, Ulm Germany
bDepartment of Nuclear Medicine, Ulm University Medical Center, Ulm, Germany
cBiozentrum of the University of Basel, Basel, Switzerland
dDepartment of Interventional Cardiology, University Hospital Maastricht, and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
* Corresponding author. Department of Interventional Cardiology, University Hospital Maastricht, P. Debyelaan 25, 6202 AZ Maastricht, The Netherlands. Tel.: +31-43-3875106; fax: +31-43-3875104. j.waltenberger{at}cardio.azm.nl
1 New address: Klinik und Poliklinik für Nuklearmedizin, Fetscherstr. 74, 01307 Dresden, Germany.
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, PlGF-2, VEGF-E plus PlGF-2 or VEGF-A plus PlGF-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 PlGF-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 arteriogenic 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.
KEYWORDS Regional blood flow; Ischemia; Animal model; Growth factor receptors; VEGF; Arteriogenesis; Endothelium; Monocytes; Collateral arteries
Abbreviations: VEGFR-1, vascular endothelial growth factor receptor-1, Flt-1 • VEGFR-2, vascular endothelial growth factor receptor-2, Klk-1/KDR • PlGF-2, placenta-derived growth factor-2 • Tc-99m-MIBI, hexakis(2-methoxyisobutylisonitrile)-technetium-99m
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