Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
J Am Heart Assoc. 2013 Sep 30;2(5):e000343. doi: 10.1161/JAHA.113.000343.
Coronary artery disease and ischemic cardiomyopathy represent the leading cause of heart failure and continue to grow at exponential rates. Despite widespread availability of coronary bypass surgery and percutaneous coronary intervention, subsequent ischemic events and progression to heart failure continue to be common occurrences. Previous studies have shown that a subgroup of patients develop collateral blood vessels that serve to connect patent and occluded arteries and restore perfusion to ischemic territories. The presence of coronary collaterals has been correlated with improved clinical outcomes; however, the molecular mechanisms governing this process remain largely unknown.
To date, no mouse models of coronary arterial growth have been described. Using a closed-chest model of myocardial ischemia, we have demonstrated that brief episodes of repetitive ischemia are sufficient to promote the growth of both large coronary arteries and the microvasculature. Induction of large coronary artery and microvascular growth resulted in improvements in myocardial perfusion after prolonged ischemia and protected from subsequent myocardial infarction. We further show that repetitive ischemia did not lead to increased expression of classic proangiogenic factors but instead resulted in activation of the innate immune system and recruitment of macrophages to growing blood vessels.
These studies describe a novel model of coronary angiogenesis and implicate the cardiac macrophage as a potential mediator of ischemia-driven coronary growth.
冠心病和缺血性心肌病是心力衰竭的主要病因，且发病率呈指数级增长。尽管冠状动脉旁路移植术和经皮冠状动脉介入治疗广泛应用，但随后的缺血事件和心力衰竭进展仍很常见。先前的研究表明，一小部分患者会形成侧支血管，这些血管可以连接通畅和阻塞的动脉，恢复缺血区域的灌注。侧支循环的存在与改善的临床结果相关；然而，控制这一过程的分子机制在很大程度上仍不清楚。
迄今为止，尚未描述冠状动脉生长的小鼠模型。我们使用了一种闭胸心肌缺血模型，证明了短暂的反复缺血足以促进大冠状动脉和微血管的生长。大冠状动脉和微血管生长的诱导导致延长缺血后的心肌灌注改善，并防止随后发生心肌梗死。我们进一步表明，反复缺血不会导致经典促血管生成因子的表达增加，而是导致固有免疫系统的激活和巨噬细胞募集到生长中的血管。
这些研究描述了一种新的冠状动脉血管生成模型，并提示心脏巨噬细胞可能是缺血驱动的冠状动脉生长的潜在介导者。
