Blood Flow Suppresses Vascular Anomalies in a Zebrafish Model of Cerebral Cavernous Malformations.

Abstract

RATIONALE\nPathological biomechanical signaling induces vascular anomalies including cerebral cavernous malformations (CCM), which are caused by a clonal loss of CCM1/KRIT1, CCM2/MGC4607, or CCM3/PDCD10. Why patients typically experience lesions only in lowly-perfused venous capillaries of the cerebrovasculature is completely unknown.\n\n\nOBJECTIVE\nIn 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.\n\n\nMETHODS AND RESULTS\nHere, 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.\n\n\nCONCLUSIONS\nThis study identifies blood flow as an important physiological factor that is protective in the etiology of this devastating vascular pathology.