Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.
Development. 2022 Sep 15;149(18). doi: 10.1242/dev.200654. Epub 2022 Sep 22.
Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.
心脏再生需要多种细胞类型来促进心肌细胞（CM）的增殖。这些细胞如何相互作用以形成生长龛尚不清楚。在这里，我们对新生小鼠心脏中心脏内皮细胞（CEC）和 CM 的增殖动力学进行了分析，发现它们在空间和时间上是偶联的。我们表明，心脏生长或再生过程中耦合的心肌血管扩张依赖于 VEGF-VEGFR2 信号，因为从 CEC 中遗传缺失 Vegfr2 或抑制 VEGFA 会消除 CEC 和 CM 的增殖。冷冻损伤后的修复显示出 CEC 和 CM 增殖的空间偶联不良。用编码 Vegfa 的病毒增加冷冻损伤后的 CEC 密度可增强再生。通过孟德尔随机化，我们证明循环 VEGFA 水平与人类心肌质量呈正相关，表明 Vegfa 可以刺激人类心脏生长。我们的工作表明了 CEC 和 CM 扩张偶联的重要性，并揭示了一个可能作为心脏再生治疗靶点的心肌血管龛。
