Efficacy and specificity of bFGF increased collateral flow in experimental peripheral arterial insufficiency

Abstract

Angiogenic growth factors could prove to be useful in managing peripheral arterial insufficiency. The present study was designed to evaluate the dose response of basic fibroblast growth factor (bFGF), the efficacy of critical routes and dosing regimens, and the specificity of action in rats with peripheral arterial insufficiency. Bilateral ligation of femoral arteries greatly reduces blood flow capacity to the calf muscles but does not impair resting flow needs. Collateral blood flow to calf muscles was determined 16 days postocclusion, during treadmill running, with (85)Sr and (141)Ce microspheres, in blinded-randomized trials that included intra-arterial and intravenous infusions and subcutaneous injections of recombinant human bFGF. Peak blood flow of 75-80 ml. min(-1). 100 g(-1) for calf muscle was observed at a bFGF dose of 5 microg. kg(-1). day(-1) (ia for 14 days) compared with 50 ml. min(-1). 100 g(-1) for vehicle groups. Similar increases in collateral blood flow were observed with short-term or prolonged and continuous or intermittent delivery of bFGF by any route. Collateral blood flows were similar in corresponding muscles across both limbs. Vascular remodeling induced by bFGF required attendant vascular occlusion, inasmuch as vessels in the normal nonoccluded vascular tree were unresponsive to circulating bFGF. Improvement in collateral blood flow with exogenous bFGF is robust, amenable to short-term administration, and requires vascular occlusion to be effective.

Time course of changes in collateral blood flow and isolated vessel size and gene expression after femoral artery occlusion in rats

“…Upon arrival, all rats were familiarized with the motor-driven treadmill by running 5-6 min/day for 4 -5 days. This brief exposure to the treadmill ensures good running performance during the training protocol and blood flow determination without developing training adaptations typical of endurance training programs (49,52).…”

“…Exogenous delivery of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) protein (16,35,45,49,57) or gene transfection (27,33), modulation of the inflammatory response (1,17), and increased physical activity (25,52,53) improve collateral blood flow and/or indexes related to improved blood flow. Interestingly, the powerful arteriogenic stimulus of exercise, which by itself leads to a markedly increased collateral blood flow, enhances the response induced by VEGF (unpublished observation) or FGF-2 (54) administration.…”

“…On the other hand, responsiveness to VEGF or FGF-2 to improve collateral blood flow occurs only in those vessels in the limb that experienced vascular occlusion. Thus even though effective doses of VEGF or FGF-2 were delivered to the corresponding vessels of the nonoccluded limbs, there was no arteriogenic response (31,49). In effect, some response within the affected vessels rendered them responsive to the angiogenic growth factor(s) and led to the increased collateral blood flow.…”

Effects of peripheral and spinal κ-opioid receptor stimulation on the exercise pressor reflex in decerebrate rats

“…Given that femoral artery ligation in the rat does not impact blood flow at rest but does reduce blood flow capacity during exercise to 10 -20% of normal (30,40), our preparation offers useful parallels to the blood flow patterns to skeletal muscle in patients with peripheral arterial disease. In addition, our findings add to previous reports from our laboratory demonstrating that peripheral -opioid and ␦-opioid receptor stimulation in rats with ligated femoral arteries (17, 37) attenuated the exercise pressor reflex.…”

“…Our laboratory recently reported, for example, that the reflex is larger in rats whose femoral arteries were ligated 72 h before the start of the experiment than it was in rats whose femoral arteries were freely perfused (36). When the femoral artery of rats is ligated, the collateral circulation provides sufficient blood flow to the hindlimb muscles when they are at rest, but does not provide sufficient flow when they are exercising (30,40). This blood flow pattern to the hindlimb muscles during both rest and exercise closely approximates the blood flow patterns to resting and exercising leg muscles of patients with peripheral arterial disease (4).…”