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Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
(2018)
Endothelial cells respond to different levels of fluid shear stress through adaptations of their mechanosensitivity. Currently, we lack a good understanding of how this contributes to sculpting of the cardiovascular system. Cerebral cavernous malformation (CCM) is an inherited vascular disease that occurs when a second somatic mutation causes a loss of CCM1/KRIT1, CCM2, or CCM3 proteins. Here, we demonstrate that zebrafish Krit1 regulates the formation of cardiac valves. Expression of heg1, which encodes a binding partner of Krit1, is positively regulated by blood-flow. In turn, Heg1 stabilizes levels of Krit1 protein, and both Heg1 and Krit1 dampen expression levels of klf2a, a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of klf2a and notch1b throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein mediated repression of klf2a and notch1b ultimately shapes cardiac valve leaflet morphology.
Over a lifetime, rhythmic contractions of the heart provide a continuous flow of blood throughout the body. An essential morphogenetic process during cardiac development which ensures unidirectional blood flow is the formation of cardiac valves. These structures are largely composed of extracellular matrix and of endocardial cells, a specialized population of endothelial cells that line the interior of the heart and that are subjected to changing hemodynamic forces. Recent studies have significantly expanded our understanding of this morphogenetic process. They highlight the importance of the mechanobiology of cardiac valve formation and show how biophysical forces due to blood flow drive biochemical and electrical signaling required for the differentiation of cells to produce cardiac valves.