Apelin signaling dependent endocardial protrusions promote cardiac trabeculation in zebrafish

Abstract

During cardiac development, endocardial cells (EdCs) produce growth factors to promote myocardial morphogenesis and growth. In particular, EdCs produce Neuregulin which is required for ventricular cardiomyocytes (CMs) to seed the multicellular ridges known as trabeculae. Defects in Neuregulin signaling, or in endocardial sprouting towards CMs, cause hypotrabeculation. However, the mechanisms underlying endocardial sprouting remain largely unknown. Here, we first show by live imaging in zebrafish embryos that EdCs interact with CMs via dynamic membrane protrusions. After touching CMs, these protrusions remain in close contact with their target despite the vigorous cardiac contractions. Loss of the CM-derived peptide Apelin, or of the Apelin receptor, which is expressed in EdCs, leads to reduced endocardial sprouting and hypotrabeculation. Mechanistically, Neuregulin signaling requires endocardial protrusions to activate extracellular signal-regulated kinase (Erk) signaling in CMs and trigger their delamination. Altogether, these data show that Apelin signaling dependent endocardial protrusions modulate CM behavior during trabeculation.

The role of Vegfc signaling during cardiac regeneration in zebrafish

“…It has been recently shown that the angiocrine molecule COL15A1 promotes CM proliferation in mice (Rhee et al, 2021). In zebrafish, the two endothelial compartments; the endocardium and coronaries play a vital role during heart development (Qi et al, 2022;Rasouli and Stainier, 2017) and regeneration (Kikuchi et al, 2011a;Lepilina et al, 2006;Marín-Juez et al, 2019;Münch et al, 2017).…”