TY - JOUR A1 - Rödel, Claudia Jasmin A1 - Otten, Cecile A1 - Donat, Stefan A1 - Lourenço, Marta Sofia Rocha A1 - Fischer, Dorothea A1 - Kuropka, Benno A1 - Paolini, Alessio A1 - Freund, Christian A1 - Abdelilah-Seyfried, Salim T1 - Blood Flow Suppresses Vascular Anomalies in a Zebrafish Model of Cerebral Cavernous Malformations JF - Circulation Research N2 - RATIONALE: Pathological biomechanical signaling induces vascular anomalies including cerebral cavernous malformations (CCM), which are caused by a clonal loss of CCM1/KRIT1 (Krev interaction trapped protein 1), CCM2/MGC4607, or CCM3/PDCD10. Why patients typically experience lesions only in lowly perfused venous capillaries of the cerebrovasculature is completely unknown. OBJECTIVE: In contrast, animal models with a complete loss of CCM proteins lack a functional heart and blood flow and exhibit vascular anomalies within major blood vessels as well. This finding raises the possibility that hemodynamics may play a role in the context of this vascular pathology. METHODS AND RESULTS: Here, we used a genetic approach to restore cardiac function and blood flow in a zebrafish model of CCM1. We find that blood flow prevents cardiovascular anomalies including a hyperplastic expansion within a large Ccm1-deficient vascular bed, the lateral dorsal aorta. CONCLUSIONS: This study identifies blood flow as an important physiological factor that is protective in the cause of this devastating vascular pathology. KW - animal models KW - cerebral cavernous malformations KW - endothelial cell KW - hemodynamics KW - zebrafish Y1 - 2019 U6 - https://doi.org/10.1161/CIRCRESAHA.119.315076 SN - 0009-7330 SN - 1524-4571 VL - 125 IS - 10 SP - E43 EP - E54 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Paolini, Alessio A1 - Fontana, Federica A1 - Van-Cuong Pham, A1 - Rödel, Claudia Jasmin A1 - Seyfried, Salim T1 - Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish JF - Cell reports N2 - In the zebrafish embryo, the onset of blood flow generates fluid shear stress on endocardial cells, which are specialized endothelial cells that line the interior of the heart. High levels of fluid shear stress activate both Notch and Klf2 signaling, which play crucial roles in atrioventricular valvulogenesis. However, it remains unclear why only individual endocardial cells ingress into the cardiac jelly and initiate valvulogenesis. Here, we show that lateral inhibition between endocardial cells, mediated by Notch, singles out Delta-like-4-positive endocardial cells. These cells ingress into the cardiac jelly, where they form an abluminal cell population. Delta-like-4-positive cells ingress in response to Wnt9a, which is produced in parallel through an Erk5Klf2-Wnt9a signaling cascade also activated by blood flow. Hence, mechanical stimulation activates parallel mechanosensitive signaling pathways that produce binary effects by driving endocardial cells toward either luminal or abluminal fates. Ultimately, these cell fate decisions sculpt cardiac valve leaflets. Y1 - 2021 U6 - https://doi.org/10.1016/j.celrep.2021.109782 SN - 2211-1247 VL - 37 IS - 1 PB - Cell Press CY - Maryland Heights, MO ER - TY - JOUR A1 - Paolini, Alessio A1 - Abdelilah-Seyfried, Salim T1 - The mechanobiology of zebrafish cardiac valve leaflet formation JF - Current opinion in cell biology : review articles, recommended reading, bibliography of the world literature N2 - 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. Y1 - 2018 U6 - https://doi.org/10.1016/j.ceb.2018.05.007 SN - 0955-0674 SN - 1879-0410 VL - 55 SP - 52 EP - 58 PB - Elsevier CY - London ER - TY - JOUR A1 - Donat, Stefan A1 - Lourenco, Marta Sofia Rocha A1 - Paolini, Alessio A1 - Otten, Cecile A1 - Renz, Marc A1 - Abdelilah-Seyfried, Salim T1 - Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis JF - eLife N2 - 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. Y1 - 2018 U6 - https://doi.org/10.7554/eLife.28939 SN - 2050-084X VL - 7 PB - eLife Sciences Publications CY - Cambridge ER -