@article{RoedelOttenDonatetal.2019,
  author    = {R{\"o}del, Claudia Jasmin and Otten, Cecile and Donat, Stefan and Louren{\c{c}}o, Marta Sofia Rocha and Fischer, Dorothea and Kuropka, Benno and Paolini, Alessio and Freund, Christian and Abdelilah-Seyfried, Salim},
  title     = {Blood Flow Suppresses Vascular Anomalies in a Zebrafish Model of Cerebral Cavernous Malformations},
  series = {Circulation Research},
  volume    = {125},
  journal   = {Circulation Research},
  number    = {10},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0009-7330},
  doi       = {10.1161/CIRCRESAHA.119.315076},
  pages     = {E43 -- E54},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@article{DonatLourencoPaolinietal.2018,
  author    = {Donat, Stefan and Lourenco, Marta Sofia Rocha and Paolini, Alessio and Otten, Cecile and Renz, Marc and Abdelilah-Seyfried, Salim},
  title     = {Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis},
  series = {eLife},
  volume    = {7},
  journal   = {eLife},
  publisher = {eLife Sciences Publications},
  address   = {Cambridge},
  issn      = {2050-084X},
  doi       = {10.7554/eLife.28939},
  pages     = {22},
  year      = {2018},
  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 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.},
  language  = {en}
}