VEGF(121)- and bFGF-induced increase in collateral blood flow requires normal nitric oxide production

The angiogenic proteins basic fibroblast growth factor (bFGF; FGF-2) and va scular endothelial growth factor 121 (VEGF(121)) are each able to enhance t he collateral-dependent blood flow after bilateral femoral artery ligation in rats. To study the effect of nitric oxide (NO) synthase (NOS) inhibition on bFGF- or VEGF(121)-induced blood flow expansion, the femoral arteries o f male Sprague-Dawley rats were ligated bilaterally, and the animals were g iven tap water [non-N-G-nitro-L-arginine methyl ester (L-NAME) group; n = 3 6] or water that contained L-NAME (L-NAME group; 2 mg/ml, n = 36). Animals from each group were further divided into three subgroups: vehicle (n = 12) , bFGF (5 mug.kg(-1).day(-1), n = 12), or VEGF(121) (10 mug.kg(-1).day(-1), n = 12). Growth factors were delivered via intra-arterial infusion with os motic pumps over days 1-14. On day 16, after a 2-day delay to permit cleara nce of bFGF and VEGF from the circulation, maximal collateral blood flow wa s determined by Sr-85- and Ce-141-labeled microspheres during treadmill run ning. L-NAME (similar to 137 mg.kg(-1).day(-1)) for 18 days increased syste mic blood pressure (similar to 26%, P < 0.001). In the absence of L-NAME, c ollateral-dependent blood flows to the calf muscles were greater in the VEG F(121)- and bFGF-treated subgroups (85 +/- 4.5 and 80 +/- 2.9 ml.min(-1).10 0 g(-1), respectively) than in the vehicle subgroup (49 +/- 3.0 ml.min(-1). 100 g(-1), P < 0.001). In the presence of NOS inhibition by L-NAME, blood f lows to the calf muscles were essentially equivalent among the three subgro ups (54 +/- 3.0, 56 +/- 5.1, and 47 +/- 2.0 ml.min(-1).100 g(-1) in the bFG F-, VEGF(121)-, and vehicle-treated subgroups, respectively) and were not d ifferent from the blood flow in the non-L-NAME vehicle subgroup. Our result s therefore indicate that normal NO production is essential for the enhance d vascular remodeling induced by exogenous bFGF or VEGF(121) in this rat mo del of experimental peripheral arterial insufficiency. These results imply that a blunted endothelial NO production could temper vascular remodeling i n response to these angiogenic growth factors.