Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Research Paper J Vasc Res 2009;46:45–54 DOI: 10.1159/000139132 Vascular Effects of FGF-2 and VEGF-B in Rabbits with Bilateral Hind Limb Ischemia Rafif Wafai Elizabeth M. Tudor James A. Angus Christine E. Wright Cardiovascular Therapeutics Unit, Department of Pharmacology, The University of Melbourne, Melbourne, Vic., Australia caused angiogenesis in the tibialis anterior muscle. Overall, VEGF-B may have advantages over FGF-2 in this setting; however, their combination may further improve arterio- genesis. Copyright © 2008 S. Karger AG, Basel Introduction Ischemic disease of the lower limb affects elderly pa- tients and many are not suitable candidates for the phar- macological, reconstructive and surgical interventions that are currently available [1]. Augmentation of either arteriogenic (development and growth of collateral arter- ies) or angiogenic (capillary growth) processes with spe- cific growth factors may improve perfusion to the isch- emic limbs of these patients [1, 2]. Many animal [3–7] and human [8–11] studies have shown an increase in vascu- larity and improvement in blood flow to ischemic limbs following angiogenic growth factor administration. The angiogenic effects of vascular endothelial growth factor (VEGF)-A, which binds to both endothelial recep- tors VEGFR-1 and VEGFR-2, have been well documented in the literature [1–3, 12]. However, the angiogenic poten- tial of VEGF-B, selective for VEGFR-1, has only recently been revealed in studies in vivo [5, 13–16]. In a mouse preparation of unilateral hind limb ischemia, Silvestre et al. [5] demonstrated that VEGF-B treatment enhanced limb perfusion, corresponding with increased arteriole Key Words Angiogenesis  Angiography, thigh vasculature  Collateral artery circulation  Growth factors  Ischemia Abstract Aims: To assess fibroblast growth factor-2 (FGF-2) and vascu- lar endothelial growth factor-B (VEGF-B) effects on flow re- serve and morphological adaptation in the rabbit ischemic hind limb. Methods: Following bilateral femoral artery liga- tion, calf blood pressure (C BP ), flow reserve, collateral artery numbers and capillary numbers were assessed. Treatment consisted of rabbit serum albumin (RSA), FGF-2, VEGF-B or FGF-2 + VEGF-B. Results: Ligation decreased C BP ; on day 14, a 48% deficit remained in the RSA group compared with a deficit of only 22% in FGF-2 and VEGF-B groups. On day 3, flow reserve was attenuated 60%, but recovered by day 14 (with no treatment effects). Collateral artery numbers in- creased with RSA (+28%), FGF-2 (+53%), VEGF-B (+47%) and FGF-2 + VEGF-B (+59%). Rectus femoris muscle total capillary profiles and fibers per cross-section were alike across groups. Tibialis anterior muscle cross-sectional area was lower with ligation and total capillary number was less in RSA and FGF- 2 groups, providing evidence for angiogenesis with VEGF-B. Capillary/muscle fiber ratio was similar in each group. Con- clusions: FGF-2 and VEGF-B enhanced lower limb perfusion as indicated by improved C BP and combined treatment in- creased collateral artery number. Flow reserve recovery was not enhanced by cytokine treatment. VEGF-B, but not FGF-2, Received: July 2, 2007 Accepted after revision: March 26, 2008 Published online: June 16, 2008 Prof. Christine E. Wright Cardiovascular Therapeutics Unit Department of Pharmacology, The University of Melbourne Melbourne, Vic. 3010 (Australia) Tel. +61 3 8344 8219, Fax +61 3 8344 0241, E-Mail cewright@unimelb.edu.au © 2008 S. Karger AG, Basel 1018–1172/09/0461–0045$24.50/0 Accessible online at: www.karger.com/jvr