Boodhwani Munir, Voisine Pierre, Ruel Marc, Sodha Neel R, Feng Jun, Xu Shu-Hua, Bianchi Cesario, Sellke Frank W
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
Eur J Cardiothorac Surg. 2008 Apr;33(4):645-50; discussion 251-2. doi: 10.1016/j.ejcts.2007.12.016. Epub 2008 Jan 16.
Growth factor based angiogenesis, with or without cell therapy, is a promising therapeutic modality for patients with coronary artery disease. We compared the relative efficacies of surgically delivered vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in a swine model of hypercholesterolemia-induced endothelial dysfunction which captures many of the pathophysiologic abnormalities of human coronary disease.
Yucatan mini-swine (20-30 kg), fed a high cholesterol diet (total 20 weeks), underwent circumflex ameroid placement to create chronic myocardial ischemia, followed three weeks later by perivascular administration of VEGF (2 microg; n=6), FGF-2 (100 microg; n=6), or placebo (n=7) in the ischemic territory. Normocholesterolemic animals (n=7) served as controls. Four weeks later, endothelial function, collateral-dependent perfusion, as well as myocardial protein and mRNA levels of angiogenic mediators were assessed.
Endothelial dysfunction was observed in all hypercholesterolemic animals as impaired microvessel relaxation in response to adenosine diphosphate and VEGF. VEGF administration improved baseline-adjusted collateral-dependent perfusion at rest (-0.03+/-0.05 vs -0.12+/-0.04, VEGF vs placebo, p=0.09), but FGF-2 delivery caused a significantly greater improvement in perfusion compared to either group (+0.15+/-0.03, p<0.05 vs HC-placebo and HC-VEGF) at rest. Molecular analysis revealed increased eNOS expression (135%+/-8%, p=0.03 vs placebo) in all growth factor treated animals and increased expression of FGF-2 receptor, FGFR1 (65+/-26%, p=0.04 vs placebo), in FGF-2 treated animals. No significant changes were demonstrated in other angiogenic mediators including Akt, Syndecan-4.
In the setting of hypercholesterolemic endothelial dysfunction, FGF-2 is more effective than VEGF at enhancing collateral-dependent perfusion and thus, may be a better candidate than VEGF for angiogenic therapy in patients with end-stage CAD.
基于生长因子的血管生成，无论是否联合细胞治疗，对于冠心病患者而言都是一种很有前景的治疗方式。我们在一个高胆固醇血症诱导的内皮功能障碍猪模型中比较了手术递送血管内皮生长因子（VEGF）和成纤维细胞生长因子-2（FGF-2）的相对疗效，该模型体现了人类冠心病的许多病理生理异常。
给体重20 - 30千克的尤卡坦小型猪喂食高胆固醇饮食（共20周），然后进行回旋支Ameroid环植入以造成慢性心肌缺血，三周后在缺血区域进行血管周围给予VEGF（2微克；n = 6）、FGF-2（100微克；n = 6）或安慰剂（n = 7）。正常胆固醇水平的动物（n = 7）作为对照。四周后，评估内皮功能、侧支循环依赖的灌注以及血管生成介质的心肌蛋白和mRNA水平。
在所有高胆固醇血症动物中均观察到内皮功能障碍，表现为对二磷酸腺苷和VEGF的微血管舒张受损。给予VEGF改善了静息时经基线调整的侧支循环依赖灌注（-0.03±0.05对-0.12±0.04，VEGF对安慰剂，p = 0.09），但与两组相比，给予FGF-2导致静息时灌注改善显著更大（+0.15±0.03，与高胆固醇血症 - 安慰剂组和高胆固醇血症 - VEGF组相比，p < ０.05）。分子分析显示，在所有生长因子治疗的动物中eNOS表达增加（135%±8%，与安慰剂相比，p = 0.03），在FGF-2治疗的动物中FGF-2受体FGFR1表达增加（65±26%，与安慰剂相比，p = 0.04）。在包括Akt、Syndecan-4在内的其他血管生成介质中未显示出显著变化。
在高胆固醇血症性内皮功能障碍的情况下，FGF-2在增强侧支循环依赖灌注方面比VEGF更有效，因此，对于终末期冠心病患者的血管生成治疗，FGF-2可能是比VEGF更好的选择。
