Important role of Placental Growth Factor on the healing process after acute myocardial infarction

背景资料：最近的研究表明，血管内皮细胞生长因子-A（VEGF-A）的治疗性血管生成在急性心肌梗死（MI）中并不总是有效的，主要是因为它只诱导不成熟的血管。胎盘生长因子（PlacentalGrowthFactor，P1 GF）是血管内皮生长因子（VEGF-A）家族的成员，其受体特异性与VEGF-A不同。PlGF特异性结合VEGF受体-I（flt-1），尽管VEGF-A结合VEGF受体1和2两者。近年来我们的临床研究表明，P1 GF在梗死心肌组织中迅速产生，血浆P1 GF水平与单核细胞和CD 34阳性细胞数及左室功能改善呈正相关。方法和结果：在C57 BL/6小鼠冠状动脉结扎前1d，通过皮下植入的渗透泵，将重组人P1 GF（rhP 1GF）10μg注入小鼠腹腔，直至结扎后2d，观察rhP 1GF对心肌梗死的治疗作用。 关于我们 行动。28天后，rhP 1GF治疗组的存活率（70.0%）显著高于PBS治疗组（33.3%）（p<0.05）。心肌梗死后7天，1.5%TTC染色，rhP 1GF治疗组心肌梗死面积（4.25± 2.04）mm ^2小于PBS组（5.95± 1.54）mm ^2，表明外源性P1 GF抑制心肌重构。超声心动图显示rhP 1GF治疗组左室舒张期内径减小（4.50±0.46mm，PBS组：5.14±0.38mm，p<0.01），射血分数增加（40.6± 9.17%，PBS组：25.7±7.23%，p<0.01）。组织学分析显示，CD 31阳性血管内皮细胞（rhP 1GF：644.6±90.54/mm ^2，PBS：459.0±73.89/mm ^2，p<0.01）和α-平滑肌肌动蛋白阳性血管rhP 1GF：31.6±7.20/mm^2，PBS：23.5±7.41/mm^2，P<0.01，提示血管新生和动脉形成均有助于心功能的改善。rhP 1GF治疗通过促进新生血管和动脉生成来保护左心室功能并抑制梗死后重构，从而提高心肌梗死后的存活率。少

Background : Recent studied indicates that therapeutic angiogenesis with vascular endothelial cell growth factor-A (VEGF-A) is not always effective in acute myocardial infarction (MI), mainly because it induces only immature vasculature. Placental growth factor (P1GF), a member of VEGF family, is different from VEGF-A in receptor specificity. P1GF specifically binds to VEGF receptor-1 (flt-1), though VEGF-A binds to both VEGF receptors 1 and 2. Recent our clinical work demonstrates that P1GF is rapidly produced within infarct myocardial tissue, and the plasma level of P1GF is positively correlated with number of monocytes and CD34 positive cells, and improvement of left ventricular function. However, therapeutic effects of P1GF on MI are not understood.Methods and Results : One day before ligation of coronary artery, recombinant human P1GF (rhP1GF) (10μg) was infused into the peritoneal cavity of C57BL/6 mice through subcutaneously implanted osmotic mini pump until 2 days after the lig … More ation. After 28 days, survival rate was significantly higher in rhP1GF-treated Group (70.0%) than PBS-Group (33.3%) (p<0.05). Seven days after MI, the infarct area, stained by 1.5% TTC (2,3,5-triphenyltetrazolium chloride), was smaller in rhP1GF-treated group (4.25±2.04mm^2) than PBS-group (5.95±1.54mm^2), and it indicates exogenous P1GF suppressed cardiac remodeling. Echocardiography also revealed that left ventricular diastolic diameter was decreased (rhP1GF: 4.50±0.46mm, PBS: 5.14±0.38mm p<0.01), and ejection fraction was increased in rhP1GF-treated group (rhP1GF: 40.6±9.17%, PBS: 25.7±7.23% p<0.01). Histological analysis showed that both CD31-positive vascular endothelial cells (rhP1GF: 644.6±90.54/mm^2, PBS: 459.0±73.89/mm^2 p<0.01) and a-smooth muscle actin-positive vessels (rhP1GF: 31.6±7.20/mm^2, PBS: 23.5±7.41/mm^2 p<0.01) was increased at infarct area, and it implied that both angiogenesis and arteriogenesis contributes to the improvement of cardiac function.Conclusion : rhP1GF-treatment preserved left ventricular function and inhibited post-infarct remodeling by enhancing neovascularization and arteriogenesis, through which rhP1GF-treatment improved survival rate after myocardial infarction. Less