Endothelial cell–cardiomyocyte crosstalk in heart development and disease

Abstract

The crosstalk between endothelial cells and cardiomyocytes has emerged as a requisite for normal cardiac development, but also a key pathogenic player during the onset and progression of cardiac disease. Endothelial cells and cardiomyocytes are in close proximity and communicate through the secretion of paracrine signals, as well as through direct cell-to-cell contact. Here, we provide an overview of the endothelial cell-cardiomyocyte interactions controlling heart Serena Zacchigna and Mauro Giacca serve as Professors of Molecular Biology at the University of Trieste, Italy and Principle Investigators of the Cardiovascular Biology and Molecular Medicine laboratories of the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Trieste, Italy, respectively. Mauro Giacca also serves as the Director-General of the ICGEB. Andrea Colliva and Luca Braga are post-docs in the same laboratories. The main research interests of Serena Zacchigna focus around the mechanisms leading to new blood vessel formation in ischaemic muscles and hearts, whereas MauroGiacca is a leader in the field of cardiac regeneration, having particular interest in understanding why mammalian cardiomyocytes permanently exit from the cell cycle at birth and how this can be overcome therapeutically. The two laboratories have been extensively collaborating over the last few years to explore the intercellular crosstalk between cardiomyocytes and cardiac endothelial cells.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 2A. Colliva and others J Physiol 00.0 development and the main processes affecting the heart in normal and pathological conditions, including ischaemia, remodelling and metabolic dysfunction. We also discuss the possible role of these interactions in cardiac regeneration and encourage the further improvement of in vitro models able to reproduce the complex environment of the cardiac tissue, in order to better define the mechanisms by which endothelial cells and cardiomyocytes interact with a final aim of developing novel therapeutic opportunities.Abstract figure legend Cardiomyocytes (labelled in red by anti-α-actinin antibodies) and endothelial cells (labelled in green by anti-CD31 antibodies) crosstalk in multiple ways, including paracrine communication (dashed arrows) through either secreted molecules or vesicles (red circles), direct cell-cell contact (hinges) and autocrine signalling (curved arrows). This crosstalk plays an important role during embryonic development, normal post-natal life and several pathological conditions, thus representing a novel target for the treatment of cardiovascular disorders.

Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity

“…In the cardiac microenvironment in vivo, each cardiomyocyte is surrounded by 3-4 capillaries with a distance between each cardiomyocyte and an endothelial cell of about 1 µm (119). This delicate build-up allows for defined cardiomyocyte-endothelium crosstalk via paracrine signaling and cell-cell contact (119)(120)(121)(122). This data suggests that the crosstalk of human cardiomyocytes with highly metabolic active cardiac endothelial cells is very important.…”

Cellular cross-talks in the diseased and aging heart

“…After cardiac injury, a major function of ECs was attributed to the control of immune cell invasion [49] via up-regulation of P-selectin [50] as well as MCP-1 [51] and the restoration of the vascular network to provide oxygen to the ischemic or hypertrophic cardiac tissue. Several studies, however, suggest that EC have important functions beyond acting as inflammatory gate keeper or oxygen pipelines [52,53]. In other organs, such as the liver or lung, a paracrine activity of ECs (so called "angiocrine" mediators) was shown to control regeneration [54,55].…”

Capturing Neonatal Cardiomyocyte – Endothelial interactions on-a-Chip

“…Crosstalk between CMs and ECs is known to stimulate the secretion of a variety of paracrine signals that regulate a range of cardiac functions such as contractility, metabolism, glucose uptake and cardiac remodelling [12,39] . The crosstalk that led to CM and EC migration that was observed in these experiments were also probably paracrine in nature.…”

“…For example, cardiomyocytes (CMs) and endothelial cells (ECs) are scattered throughout the endocardium and myocardium [8,9] , and it is challenging to pinpoint the fate of individual cells within a thick complex tissue. This is one of the reasons why the morphogenetic steps involved in CMs and ECs migration and differentiation during cardiac development are still not well defined [10][11][12] . It is even harder to identify precise cell-cell interactions between CMs and ECs in this setting.…”

“…CD31 expressing ECs are a major constituent of the coronary vasculature [22] . Several groups have investigated the co-culture of CMs and ECs [12,[23][24][25] . These 4 studies have involved the use of adult CMs or CMs derived from either induced pluripotent stem cells (iPSC) [26] , or human embryonic stem cells (hESC) [27] .…”