Abstract
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.
Highlights
The survival of ischaemic cardiomyocytes after myocardial infarction (MI) depends on the formation of new blood vessels
We instead examined the cardiac activity of the HLX-3:LacZ enhancer:reporter transgene, which is directly activated by the vascular endothelial growth factor A (VEGFA)-MEF2 pathway in endothelial cells (ECs): the HLX-3 enhancer, located 3 kb upstream of the homeobox transcription factor HLX, activates gene expression during sprouting angiogenesis in the systemic vasculature via direct and essential MEF2 binding[19] (Fig. 1a)
The results presented so far suggest that the VEGFA-MEF2 angiogenic and SOXF/RBPJ regulatory pathways are active in distinct populations of ECs within the heart
Summary
The survival of ischaemic cardiomyocytes after myocardial infarction (MI) depends on the formation of new blood vessels. Endothelial heterogeneity is a fundamental feature of the systemic vasculature: differential gene expression in specific endothelial sub-populations is essential for vasculogenesis and angiogenesis; for the creation of the hierarchically branched vascular system of arteries, veins and lymphatics; and for organ specialisation in response to local signals[4,5,6]. This structural and functional heterogeneity is matched by extensive regulatory heterogeneity, with independent signalling and transcriptional pathways controlling the growth of different endothelial sub-populations[7,8,9]. Our lab and others have recently characterised and analysed a number of enhancers that drive gene expression to discrete sub-populations of ECs, clearly demonstrating important roles for epigenetic modification and transcription factor combinations in achieving distinct patterns of gene expression[7,18,19,20,21,22,23]
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