Impact of Lymphangiogenesis on Cardiac Remodeling After Ischemia and Reperfusion Injury.
Impact of Lymphangiogenesis on Cardiac Remodeling After Ischemia and Reperfusion Injury.
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DOI：
10.1161/jaha.118.009565
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发表时间：
2018-10-02
影响因子：
5.4
通讯作者：
Calvert JW
中科院分区：
文献类型：
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作者：
Shimizu Y;Polavarapu R;Eskla KL;Pantner Y;Nicholson CK;Ishii M;Brunnhoelzl D;Mauria R;Husain A;Naqvi N;Murohara T;Calvert JW
淋巴管与血管相互连接，形成一个复杂的系统，帮助控制组织压力和水肿的形成。虽然已知淋巴系统存在于心脏中，但对心脏淋巴系统在心力衰竭的发展中所起的作用知之甚少。小鼠（C57BL/6J，雄性，8 ~ 12周龄）分别进行心肌缺血或心肌缺血再灌注28天。分析显示，两种模型均在损伤后第1天开始增加血管内皮生长因子C和VEGF受体3的蛋白表达，而在第3天开始观察到淋巴管密度显著增加。进一步的研究旨在确定抑制内源性淋巴管生成反应对心力衰竭发展的影响。使用两种不同的药理学方法，我们发现用MAZ‐51抑制VEGF受体3和用中和抗体阻断内源性血管内皮生长因子C可以减弱淋巴管密度的增加、淋巴运输的减弱、炎症的增加、水肿的增加和心功能障碍的增加。随后的研究表明，血管内皮生长因子C治疗可以增强内源性淋巴管生成反应，减轻炎症，减轻水肿，改善心功能障碍。这些结果表明，内源性淋巴管生成反应在缺血性心力衰竭的发展中起着适应性作用，并支持了治疗性淋巴管生成是治疗心血管疾病的一种有前途的新方法的新兴概念。
Lymphatic vessels interconnect with blood vessels to form an elaborate system that aids in the control of tissue pressure and edema formation. Although the lymphatic system has been known to exist in a heart, little is known about the role the cardiac lymphatic system plays in the development of heart failure. Mice (C57BL/6J, male, 8 to 12 weeks of age) were subjected to either myocardial ischemia or myocardial ischemia and reperfusion for up to 28 days. Analysis revealed that both models increased the protein expression of vascular endothelial growth factor C and VEGF receptor 3 starting at 1 day after the onset of injury, whereas a significant increase in lymphatic vessel density was observed starting at 3 days. Further studies aimed to determine the consequences of inhibiting the endogenous lymphangiogenesis response on the development of heart failure. Using 2 different pharmacological approaches, we found that inhibiting VEGF receptor 3 with MAZ‐51 and blocking endogenous vascular endothelial growth factor C with a neutralizing antibody blunted the increase in lymphatic vessel density, blunted lymphatic transport, increased inflammation, increased edema, and increased cardiac dysfunction. Subsequent studies revealed that augmentation of the endogenous lymphangiogenesis response with vascular endothelial growth factor C treatment reduced inflammation, reduced edema, and improved cardiac dysfunction. These results suggest that the endogenous lymphangiogenesis response plays an adaptive role in the development of ischemic‐induced heart failure and supports the emerging concept that therapeutic lymphangiogenesis is a promising new approach for the treatment of cardiovascular disease.