Napoleone Ferrara

Synergistic Effect of Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor on Angiogenesis In Vivo

BACKGROUNDnRecent studies have suggested that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) may have synergistic effects on the induction of angiogenesis in vitro. Therefore, we investigated the hypothesis that the simultaneous administration of VEGF and bFGF, each having been previously shown to independently enhance collateral development in an animal model of hind limb ischemia, could have a synergistic effect in vivo.nnnMETHODS AND RESULTSnTen days after surgical induction of unilateral hind limb ischemia, New Zealand White rabbits were randomized to receive either VEGF 500 micrograms alone (n = 6), bFGF 10 micrograms alone (n = 7), VEGF 500 micrograms, immediately followed by 10 micrograms bFGF (n = 7), or vehicle only (control animals, n = 8) in each case administered intra-arterially via a catheter in the internal iliac artery of the ischemic limb. BP ratio (BPR, ischemic/healthy limb) at day 10 for the VEGF+bFGF group was 0.82 +/- 0.01, much superior (P < .0005) to that of either the VEGF group (0.52 +/- 0.02) or the bFGF group (0.57 +/- 0.02). This outcome persisted at day 30: BPR in the VEGF+bFGF group (0.91 +/- 0.02) exceeded that of the control group (0.49 +/- 0.05, P < .0001), the VEGF group (0.65 +/- 0.03, P < .0005), or the bFGF group (0.66 +/- 0.03, P < .0005). Serial angiography demonstrated a progressive increase in luminal diameter of the stem collateral artery and the number of opacified collaterals in the thigh of the ischemic limbs in all groups. Stem artery diameter with VEGF+bFGF (1.34 +/- 0.07 mm) on day 30 was significantly (P < .05) greater than with either VEGF (1.09 +/- 0.09) or bFGF (1.18 +/- 0.06) alone. Capillary density was significantly greater (P < .05) in VEGF+bFGF animals (275 +/- 20 mm2) compared with VEGF (201 +/- 8) or bFGF (209 +/- 15).nnnCONCLUSIONSnCombined administration of VEGF and bFGF stimulates significantly greater and more rapid augmentation of collateral circulation, resulting in superior hemodynamic improvement compared with either VEGF or bFGF alone. This synergism of two angiogenic mitogens with different target cell specificities may have important implications for the treatment of severe arterial insufficiency in patients whose disease is not amenable to direct revascularization.

Vascular Endothelial Growth Factor Attenuates Myocardial Ischemia-Reperfusion Injury

BACKGROUNDnHypoxic endothelial cell activation plays a key role in the myocardial dysfunction resulting from ischemia-reperfusion injury. Recent evidence suggests that vascular endothelial growth factor (VEGF) may, in addition to promoting angiogenesis, modulate various aspects of endothelial function and repair. We examined whether administration of VEGF in the cardioplegic solution might have a beneficial effect on myocardial ischemia-reperfusion injury in an isolated rat heart model.nnnMETHODSnHearts from Sprague-Dawley rats were perfused with Krebs-Henseleit solution in a modified Langendorff apparatus. Percent recovery of cardiac output, coronary flow, stroke work, and percent increase in coronary vascular resistance were measured after 2 hours of global ischemia and 40 minutes of reperfusion. Coronary effluent was collected after ischemia and reperfusion for measurement of creatine kinase.nnnRESULTSnHearts receiving cardioplegia solution containing 125 microg VEGF showed significantly improved recovery of cardiac output, coronary flow, and stroke work, and significantly reduced coronary vascular resistance compared with hearts receiving hyperkalemic cardioplegia only (p < 0.05). Coadministration of a nitric oxide synthase inhibitor attenuated the VEGF-induced cardiprotective effects. Hearts treated with VEGF released significantly less creatine kinase compared with control hearts.nnnCONCLUSIONSnAddition of VEGF to hyperkalemic cardioplegia protects against myocardial ischemia-reperfusion injury in the isolated rat heart.