Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis

Abstract

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 <i>heg1</i>, 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 <i>klf2a,</i> a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of <i>klf2a</i> and <i>notch1b</i> throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein-mediated repression of <i>klf2a</i> and <i>notch1b</i> ultimately shapes cardiac valve leaflet morphology.