胎盘生长因子恢复急性心肌梗死大鼠心功能及其机制

Effects of placental growth factor on revascularization after acute myocardial infarction in rats

目的：探讨胎盘生长因子（PIGF）及其受体（VEGFR1）在急性心肌梗死后心功能恢复中的作用。方法：采用结扎Wistar大鼠左冠状动脉前降支的方法建立急性心肌梗死模型。建模型成功后随机将30只Wistar大鼠分为对照组、PIGF组、抗VEGFR1抗体组，于心肌梗死区分别注射生理盐水、PIGF、鼠抗VEGFR1抗体。术后2周观测各组大鼠心功能，然后经股静脉注射2ml 15％氯化钠溶液处死大鼠，制作心脏病理切片评估左心室结构，免疫组织化学法检测冯·维勒布兰德因子（vWF）和α平滑肌肌动蛋白（α-SMA），分析心肌梗死区域的新生血管，以及TUNEL法检测心肌梗死区心肌细胞凋亡情况。结果：PIGF组大鼠心肌血流动力学指标每搏输出量、收缩压／舒张压、左心室峰压、左心室发展峰压、左心室舒张末压明显优于对照组（均P〈0．01）；PIGF组大鼠左心室直径、心室梗死交界区室壁厚度均小于对照组（均P〈0．01），抗VEGFR1抗体组与对照组的心脏几何学参数基本一致；PIGF组大鼠新生血管和动脉密度均高于对照组（P〈0．01），抗VEGFR1抗体组的动脉密度略低于对照组，差异无统计学意义（P〉0．05）；PIGF组大鼠心肌细胞凋亡率明显低于对照组（P〈0．01）。结论：急性心肌梗死大鼠心肌局部注射PIGF可显著改善心功能恢复并抑制左心室扩张，促进血管再生并降低心肌细胞凋亡。PIGF治疗有望作为急性心肌梗死患者综合治疗中的一个辅助性手段。

Objective： To investigate the effect of placental growth factor （PIGF） on revascularization after acute myocardial infarction. Methods： Myocardial infarction model was established by ligation of left anterior descending coronary artery in Wistar rats. Thirty AMI rats were divided into 3 groups with 10 in each group： PIGF, mouse VEGFR-1/Flt-1 antibody, or saline （control group） was injected in the infarcted border zone for each group, respectively. Two weeks later the hemodynamics parameters were measured with a left ventricular needle catheter and a biological signal analysis system; left ventricular remodeling was observed by H＆E staining; angiogenesis was examined by immunohistochemistry and cardiomyocyte apoptosis rate was detected by TUNEL. Results： The stroke volume, systolic pressure and left ventricular developed pressure in PIGF group were all higher than those in control group （112 ± 7 vs 65.63 ± 8.50 μl, P 〈0.01; 131. 61 ±9. 26 vs 94.84 ±8. 53 mm Hg, P 〈0. 01 and 175.85 ± 11. 36 vs 105.50 ± 15.83 mm Hg , P 〈 0.01; respectively）. PIGF animals had less ventricular dilation （left ventricular diameter 8.20 ± 0. 14 vs 9.25 ± 0.32 mm, P 〈 0. 01） and increased left ventricular wall thickness （1. 81 ± 0. 10 vs 1. 35 ± 0. 10 mm, P 〈 0. 01 ） compared to controls. The geometry parameter of anti-VEGFR1 and control animals was almost the same. PIGF animals had increased angiogenesis compared to controls （ 29. 44 ± 5. 75 vs 15. 88 ± 2. 42 endothelial cells/high-powered field, P 〈 0. 01 ） ; the alpha smooth muscle actin （α-SMA） showed that PIGF animal had a higher density of artery than others （25. 14 ± 1. 83 vs 19. 70 ± 2.52 arteries/mm^2, P 〈 0.01）, and the density of artery in anti- VEFGR1 group was less than the controls. The apoptosis rate of cardiomyocytes in PIGF animals was significantly lower than that in controls （9. 51 ± 2.75 vs 37. 81 ± 8. 74 %, P 〈 0. 01 ）. Conclusion： Regional delivery of PIGF following acute myocardial infarction can improve cardiac function and left ventricular remodeling, enhance angiogenesis and reduce cardiomyocyte apoptosis rate. PIGF may be a potential agent in adjuvant therapy for acute myocardial infarction.