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  - 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  -