ABSTRACT
Vascular endothelial growth factor C (Vegfc) is crucial for lymphatic and blood vessel development, yet its cellular sources and specific functions in heart development remain unclear. To address this, we created a vegfc reporter and an inducible overexpression line in zebrafish. We found vegfc expression in large coronary arteries, circulating thrombocytes, cardiac adipocytes, and outflow tract smooth muscle cells. Notably, although coronary lymphangiogenesis aligns with Vegfc-expressing arteries in juveniles, it occurs only after coronary artery formation. Vegfc overexpression induced ectopic lymphatics on the ventricular surface prior to arterial formation, indicating that Vegfc abundance, rather than arterial presence, drives lymphatic development. However, this overexpression did not affect coronary artery coverage, suggesting a specific role for Vegfc in lymphatic, rather than arterial, development. Thrombocytes emerged as the initial Vegfc source during inflammation following heart injuries, transitioning to endocardial and myocardial expression during regeneration. Lower Vegfc levels in an amputation model corresponded with a lack of lymphatic expansion. Importantly, Vegfc overexpression enhanced lymphatic expansion and promoted scar resolution without affecting cardiomyocyte proliferation, highlighting its role in regulating lymphangiogenesis and promoting heart regeneration.
Footnotes
Author contributions
Conceptualization: M.R.M.H., J.C.; Methodology: M.R.M.H., J.C.; Investigation: S.D., Y.X., L.A.E., I.B., M.Q., Y.C., Y.G., J.K.; Resources: J.V.E., M.L.M., M.R.M.H., J.C.; Writing - original draft: S.D., J.C.; Writing - review & editing: S.D., Y.X., J.K., M.R.M.H., J.C.; Supervision: J.C.; Funding acquisition: J.K., M.R.M.H., J.C.
Funding
This work was supported by the National Institutes of Health (NIH) (predoctoral training grant position T32-HD060600 and predoctoral fellowship F31-HL158168 to S.D.; R01HL151522 to J.K.; R01NS126209 to M.R.M.H.; R01HL155607 and R01HL166518 to J.C.), a fellowship from The Louis and Rachel Rudin Foundation (Y.X.), and an American Heart Association (AHA) Career Development Award (AHA941434 to M.R.M.H.). Deposited in PMC for release after 12 months.
Data availability
All relevant data can be found within the article and its supplementary information.
