Interplay between cardiac function and heart development

Abstract

Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease. This requires cardiomyocytes to be mechanically durable and able to mount coordinated responses to a variety of environmental signals on different time scales, including cardiac pressure loading and electrical and hemodynamic forces. During physiological growth, myocytes, endocardial and epicardial cells have to adaptively remodel to these mechanical forces. Here we review some of the recent advances in the understanding of how mechanical forces influence cardiac development, with a focus on fluid flow forces. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Keywords: Blood and pericardial flow; Cardiac development; Mechanosensing; Mechanotransduction; Mouse; Zebrafish.

Fig. 1

Stages of cardiac development in the mouse and the zebrafish. The heart is subjected to the flow of blood (black arrows) and pericardial fluid (blue arrows) during most developmental stages and throughout adult life. Illustrations show ventral views of hearts. (A) Mouse heart development. The most important events taking place are listed. (B) Zebrafish heart development. In both animal models, laminar flow becomes turbulent at the site of valve formation. (C) Blood pressure across developmental stages in different animal models (modified from [81]). Endocardium is marked green, myocardium red, epicardium blue, and the developing valves yellow. Blue circles represent proepicardial cells. Dotted lines illustrate turbulent flow or oscillatory flow at valves. A, atrium; AVC, atrioventricular canal; bpm, beats per minute; LA, left atrium; LV, left ventricle; OFT, outflow tract; PE, proepicardium; RA, right atrium; RV, right ventricle; V, ventricle.

Fig. 2

Mechanical forces influencing cardiac development. Inside the heart, the blood is in direct contact with the endocardium and exerts shear force on the endocardium and cyclic strain on the three heart layers. Outside the heart, the pericardial fluid generates a shear stress force on the epicardium and pericardium as well as pressure on the whole heart. The illustration shows a section of the heart wall. Arrows indicate force vectors.

Fig. 3

Mechanosensors and mechanotransduction pathways involved in cardiac development. Transduction of blood forces to the cells forming the heart. White boxes indicate the final effect of mechanical forces in the different cell types. On the cell surface of endocardial cells, primary cilia, ion channels Trpv4/Trpp2 and integrins can act as mechanosensors. The lateral cell membrane contains the cell–cell adhesion complexes such the cadherin/catenin complex, which bind to their counterparts on adjacent cells. Tension is transmitted to the lateral borders and basal membrane, where adhesion receptors or integrins experience changes in tension. Within the cortical actin cytoskeleton, actin stress fibers mechanically connect different regions of the cell. Integrin-dependent complexes anchor the cells to the basement membrane. Klf2 plays a central role as a mechanotransducer. In cardiomyocytes, the α-catenin-YAP axis plays a major role in mechanotransduction. Nitric oxide and Endothelin signaling are important for propagation of the effect of mechanical forces between neighboring tissues e.g. from endothelial cells to cardiomyocytes and fibroblasts. Mechanical forces also control TGF-β activity. ECM, extracellular matrix; N, nucleus. Rest of abbreviations are explained in the main text.