Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Nat Commun. 2019 Jul 22;10(1):3276. doi: 10.1038/s41467-019-10710-2.
The survival of ischaemic cardiomyocytes after myocardial infarction (MI) depends on the formation of new blood vessels. However, endogenous neovascularization is inefficient and the regulatory pathways directing coronary vessel growth are not well understood. Here we describe three independent regulatory pathways active in coronary vessels during development through analysis of the expression patterns of differentially regulated endothelial enhancers in the heart. The angiogenic VEGFA-MEF2 regulatory pathway is predominantly active in endocardial-derived vessels, whilst SOXF/RBPJ and BMP-SMAD pathways are seen in sinus venosus-derived arterial and venous coronaries, respectively. Although all developmental pathways contribute to post-MI vessel growth in the neonate, none are active during neovascularization after MI in adult hearts. This was particularly notable for the angiogenic VEGFA-MEF2 pathway, otherwise active in adult hearts and during neoangiogenesis in other adult settings. Our results therefore demonstrate a fundamental divergence between the regulation of coronary vessel growth in healthy and ischemic adult hearts.
心肌梗死后缺血性心肌细胞的存活依赖于新血管的形成。然而，内源性血管新生效率低下，指导冠状动脉生长的调节途径尚不清楚。在这里，我们通过分析心脏中差异调节的内皮增强子的表达模式，描述了发育过程中冠状动脉中三种独立的调节途径。血管生成 VEGFA-MEF2 调节途径主要在心内膜衍生的血管中活跃，而 SOXF/RBPJ 和 BMP-SMAD 途径分别见于窦房结静脉衍生的动脉和静脉冠状血管。尽管所有发育途径都有助于新生儿心肌梗死后的血管生长，但在成年心脏梗死后的血管新生过程中，没有任何途径是活跃的。这在血管生成 VEGFA-MEF2 途径中尤为明显，该途径在成年心脏中活跃，并且在其他成年环境中的新血管生成中活跃。因此，我们的研究结果表明，健康和缺血性成年心脏中冠状动脉生长的调节存在根本差异。
