Coronary endothelial lineage and hypoxia-mediated myovascular coupling in cardiac development and regeneration
Description: Myocardial infarction causes over 600,000 US deaths annually, yet no therapies exist to replace damaged cardiac tissue. This bridge funding continues to support critical work addressing fundamental questions about optimal cardiac vascularization for regenerative medicine. Our CDA research revealed compact cardiomyocyte (CM) formation is spatiotemporally coordinated with coronary endothelial cells (ECs) and hypoxia-responsive epicardial cells during zebrafish heart development and regeneration. Rather than direct CM-EC communication as initially proposed, we identified hypoxia-regulated epicardial genes (HREGs) consistently expressed adjacent to coronary sprouts and expanding CMs that drive coupled expansion via respective negative regulation and positive feedback. We propose to build on this with the following aims: Aim 1 defines the 3-dimensional epicardial hypoxia landscape during ventricle development and its impact on coronary vasculature and myocardial expansion. Using transgenic zebrafish providing in vivo oxygen readouts (hsp:DsRed-FT, glut1b:mCherry), we will map regional hypoxia differences and metabolic shifts. Live imaging will reveal spatial associations between epicardial subsets, coronary ECs, and compact CMs. We will determine hypoxia’s impact using epicardium-specific constitutively active or dominant-negative Hif1a alleles, quantifying HREG expression. Aim 2 defines EC lineage relationships and plasticity during coronary development and regeneration. We will investigate embryonic origins of coronary sprouts using lyve1:CreER and dab2:CreER lineage tracing, testing whether tip ECs become coronary arteries but originate from venous-identity endocardium. For regeneration, we will track endocardial contribution using our endo83:CreER line and test whether dab2 overexpression increases angiogenic potential. Our CDA has generated two submitted manuscripts, contributed to five publications, with one additional submission expected, and four NHLBI applications with competitive but as yet unfunded scores. This proposal will define functional cardiac growth and vascularization mechanisms, provide critical data for grant resubmissions, and complete two manuscripts. Federal funding delays and budget constraints created temporary personnel support gaps, threatening the momentum of a program that would advance AHA’s mission by elucidating cellular and molecular mechanisms of heart regeneration, enabling novel therapies to repair damaged human hearts.
Funder: American Heart Association
Amount: $77,000
Funding type: fellowship
Funder scheme: Bridge Career Development Award
Start date: 2026-04-01
End date: 2027-03-31
Investigators: Michael Harrison, Michael Harrison
Institution: Weill Medical College of Cornell University
Funded outputs count: 0
Funder award ID: 26BCDA1622764
OpenAlex ID: G7609920920