Mécanotransduction des forces hémodynamiques et organogenèse

Abstract

Selon de nombreuses études in vitro, la cellule endothéliale cardiovasculaire serait capable de percevoir les variations mécaniques de son environnement immédiat - la circulation sanguine - et de les convertir en messages biologiques complexes (remodelage cytosquelettique, régulation de l’expression génique, signalisation intercellulaire). Néanmoins, en raison de la létalité souvent inhérente à l’expérimentation sur le système cardiovasculaire, le rôle de la mécanotransduction des cellules endothéliales in vivo demeure méconnu. De nouvelles expériences de blocage du flux sanguin réalisées chez l’embryon de poisson- zèbre - un modèle animal dont l’oxygénation tissulaire ne dépend pas du système cardiovasculaire - révèlent un rôle essentiel de la mécanotransduction endothéliale dans l’organogenèse, en particulier cardiaque. Ces découvertes suggèrent que certaines cardiomyopathies humaines pourraient résulter d’anomalies de l’hémodynamique et/ou de l’activité transductionnelle des cellules endothéliales, et réaffirment l’importance de la contribution épigénétique dans le contrôle du développement embryonnaire.

Endothelial cells (EC) of the vertebrate cardiovascular system (CVS) are bona fide, yet enigmatic mechanoreceptors. When cultured in vitro and exposed to fluid forces, EC modify their physiological behaviour at the structural, metabolical and gene expression levels in response to the mechanical stimulus. However, as a direct consequence of the hypoxic bias (and often the lethality) that results from blocking blood flow in most animal systems, the in vivo role of EC mechanosensation (ECMS) remains poorly understood. The zebrafish has recently emerged as an alternative genetic model for the study of vertebrate development. Its striking ability to survive until larval stages in the absence of blood circulation circumveys the usual caveats that are inherent to CVS research, and offers the exciting opportunity to dissect the function of ECMS in vivo. Two groups have already uncovered an essential role for ECMS in zebrafish organogenesis, particularly in heart morphogenesis. In embryos in which intracardiac blood flow is genetically or physically compromised, several features of the normally developing heart, including valve formation, are specifically disrupted. In addition, impressive imaging studies of zebrafish hemodynamics demonstrate that the shear stress exerted upon the cardiac endothelium is largely in the range of the stimulus that in vitro activates cytoskelettal remodeling and gene expression changes in EC. Hence the cardiac phenotypes observed in vivo may indeed directly result from a lack of ECMS-dependent EC activity. These data shed first light on the role of ECMS in vivo. Notably, they also suggest that a number of human congenital cardiomyopathies may arise through abnormal fetal hemodynamics and/or EC sensory activity. Finally, these discoveries reinforce the too often neglected role of epigenetic factors (in this case, fluid forces) in the regulation of animal development.