Division of Clinical Cardiology and Department of Cardiovascular Sciences, Gasthuisberg University Hospitals, Leuven, Belgium.
Am J Physiol Heart Circ Physiol. 2013 Mar 15;304(6):H885-94. doi: 10.1152/ajpheart.00587.2012. Epub 2013 Jan 11.
Placental growth factor (PlGF) has a distinct biological phenotype with a predominant proangiogenic role in disease without affecting quiescent vessels in healthy organs. We tested whether systemic administration of recombinant human (rh)PlGF improves regional myocardial blood flow (MBF) and systolic function recovery in a porcine chronic myocardial ischemia model. We implanted a flow-limiting stent in the proximal left anterior descending coronary artery and measured systemic hemodynamics, regional myocardial function using MRI, and blood flow using colored microspheres 4 wk later. Animals were then randomized in a blinded way to receive an infusion of rhPlGF (15 μg·kg(-1)·day(-1), n = 9) or PBS (control; n = 10) for 2 wk. At 8 wk, myocardial perfusion and function were reassessed. Infusion of rhPlGF transiently increased PlGF serum levels >30-fold (1,153 ± 180 vs. 33 ± 18 pg/ml at baseline, P < 0.001) without affecting systemic hemodynamics. From 4 to 8 wk, rhPlGF increased regional MBF from 0.46 ± 0.11 to 0.85 ± 0.16 ml·min(-1)·g(-1), with a concomitant increase in systolic wall thickening from 11 ± 3% to 26 ± 5% in the ischemic area. In control animals, no significant changes from 4 to 8 wk were observed (MBF: 0.45 ± 0.07 to 0.49 ± 0.08 ml·min(-1)·g(-1) and systolic wall thickening: 14 ± 4% to 18 ± 1%). rhPlGF-induced functional improvement was accompanied by increased myocardial neovascularization, enhanced glycogen utilization, and reduced oxidative stress and cardiomyocyte apoptosis in the ischemic zone. In conclusion, systemic rhPlGF infusion significantly enhances regional blood flow and contractile function of the chronic ischemic myocardium without adverse effects. PlGF protein infusion may represent an attractive therapeutic strategy to increase myocardial perfusion and energetics in chronic ischemic cardiomyopathy.
胎盘生长因子（PlGF）具有独特的生物学表型，在疾病中主要发挥促血管生成作用，而不会影响健康器官中静止的血管。我们在猪慢性心肌缺血模型中测试了全身性给予重组人（rh）PlGF 是否能改善局部心肌血流（MBF）和收缩功能的恢复。我们在左前降支近段植入了一个限制血流的支架，4 周后使用 MRI 测量全身血液动力学、局部心肌功能和血流，并使用彩色微球进行测量。然后，动物随机分为两组，接受 rhPlGF 输注（15μg·kg(-1)·天(-1)，n = 9）或 PBS（对照组；n = 10），为期 2 周。8 周时，重新评估心肌灌注和功能。rhPlGF 输注使 PlGF 血清水平升高超过 30 倍（从基线的 1153±180pg/ml 增加至 33±18pg/ml，P＜0.001），而不影响全身血液动力学。从第 4 周到第 8 周，rhPlGF 增加了缺血区的局部 MBF 从 0.46±0.11ml·min(-1)·g(-1)增加至 0.85±0.16ml·min(-1)·g(-1)，同时，缺血区的收缩壁增厚从 11±3%增加至 26±5%。在对照组动物中，从第 4 周到第 8 周没有观察到明显变化（MBF：0.45±0.07ml·min(-1)·g(-1)增加至 0.49±0.08ml·min(-1)·g(-1)，收缩壁增厚：14±4%增加至 18±1%）。rhPlGF 诱导的功能改善伴随着缺血区心肌新生血管形成增加、糖原利用增加、氧化应激和心肌细胞凋亡减少。总之，全身性 rhPlGF 输注可显著增加慢性缺血心肌的局部血流和收缩功能，而无不良影响。PlGF 蛋白输注可能是增加慢性缺血性心肌病心肌灌注和能量的一种有吸引力的治疗策略。
