Recovery of disturbed endothelium-dependent flow in the collateral-perfused rabbit ischemic hindlimb after administration of vascular endothelial growth factor

Abstract

Background: Disturbed endothelium-dependent blood flow has been shown to be a feature of native collateral vessels. Recent studies have shown that recombinant angiogenic growth factors augment collateral development in animal models of hindlimb ischemia. We therefore investigated the hypothesis that the administration of an angiogenic growth factor, in this case vascular endothelial growth factor (VEGF), may promote recovery of disturbed endothelium-dependent blood flow in a rabbit model of hindlimb ischemia.

Methods and results: Ischemia was induced by ligation of the external iliac artery and excision of the femoral artery in one limb of New Zealand White rabbits (day 0). Flow velocity was measured using a Doppler guide wire at rest and after administration of serotonin and acetylcholine. Blood flow (in mL/min) was calculated assuming a circular lumen geometry. In untreated control animals with an ischemic limb, serotonin administered at day 10 or 40 produced a decrease in hindlimb blood flow (71 +/- 2% and 33 +/- 6% reduction from baseline, respectively); in contrast, among animals treated with a single 500-micrograms bolus dose of VEGF administered selectively into the internal iliac artery at day 10 and studied at day 40, serotonin produced an increase in flow (119 +/- 8% from baseline; P < .05 versus control animals). Acetylcholine induced only a moderate increase in flow in control animals (152 +/- 15% at day 10 and 177 +/- 14% at day 40) in contrast to a profound increase among VEGF-treated animals studied at day 40 (254 +/- 25%; P < .05 versus control animals).

Conclusions: To our knowledge, these findings constitute the first demonstration of successful pharmacological modulation of disturbed endothelium-dependent flow in the arterial circulation subserved by collateral vessels. This physiological benefit complements previously reported anatomic findings suggesting a favorable impact of angiogenic growth factors on collateral-dependent limb ischemia.