Endothelial-cardiomyocyte interactions in cardiac development and repair

Abstract

Communication between endothelial cells and cardiomyocytes regulates not only early cardiac development but also adult cardiomyocyte function, including the contractile state. In the normal mammalian myocardium, each cardiomyocyte is surrounded by an intricate network of capillaries and is next to endothelial cells. Cardiomyocytes depend on endothelial cells not only for oxygenated blood supply but also for local protective signals that promote cardiomyocyte organization and survival. While endothelial cells direct cardiomyocytes, cardiomyocytes reciprocally secrete factors that impact endothelial cell function. Understanding how endothelial cells communicate with cardiomyocytes will be critical for cardiac regeneration, in which the ultimate goal is not simply to improve systolic function transiently but to establish new myocardium that is both structurally and functionally normal in the long term.

Figure 1

Endothelial-cardiomyocyte assembly in adult mouse myocardium. Normal adult mouse myocardium is stained with intravital perfusion techniques to demonstrate cardiomyocyte (outlined in red) and capillary (green; stained with isolectin-fluorescein) assembly. Nuclei are blue (Hoechst). Original magnification: 600X.

Figure 2

Endothelial-cardiomyocyte interactions through autocrine and paracrine signaling. Endothelial cells may secret signaling mediators modulating cardiomyocyte development (neuregulin, PDGF-B, and NF1), survival (neuregulin and PDGF-B), and contraction (NO and ET-1). Reciprocally, cardiomyocytes may also promote endothelial cell survival and assembly through VEGF-A and angiopoietin-1. Even more complicated is combined autocrine and paracrine signaling between endothelial cells and cardiomyocytes through ET-1 and angiopoietin-1. PDGF-B, platelet-derived growth factor-B; PDGFR-β, PDGF receptor-β; NF1, neurofibromatosis type 1; NO, nitric oxide; ET-1, endothelin-1; VEGF-A, vascular endothelial growth factor-A.

Figure 3

Mechanisms of myocardial regeneration through endothelial and endothelial progenitor cell therapies. After injury to a site, cardiomyocytes undergo apoptosis and necrosis and release cytokines and chemoattractants to recruit endothelial cells (EC) and endothelial progenitor cells (EPC) to the site. EC/EPC are activated and may promote myocardial regeneration through different mechanisms, including (a) releasing cardiomyocyte survival factors to protect fragile cardiomyocytes, (b) promoting differentiation of resident cardiac stem cells or progenitors for population into the injured area, (c) undergoing transdifferentiation into cardiomyocytes to replace dead cells, and (d) fusing with cardiomyocytes to facilitate cell proliferation for repair.