Reversal of vein of Galen aneurysmal malformation by stimulation of flow-mediated vessel fusion

Abstract

Congenital vascular malformations arise from defective homeostatic development of the vascular tree1. The aneurysmal malformation of the Vein of Galen (VGAM) is the most frequent neurovascular malformation in neonates, with limited therapeutic options and poor outcomes in the most severe cases2. This congenital disease is consecutive to germline genetic mutation of RASA1 or EPHB43,4, but little is known about the mechanisms leading to its development. We generated mutant rasa1a and ephb4a deficiency models in zebrafish reproducing the genetic and structural characteristics of the VGAM in the dorsal longitudinal vein of the cerebral vasculature. We link the development of the malformation to a failure of the fusion of precursor blood vessels into a draining vessel for the choroidal type malformations and to a failure to constrict for the mural type malformations. The fusion process is driven by blood flow, sensed and integrated by endothelial cells. RASA1 deficiency destabilizes the homeostatic response to blood flow and contributes to impaired flow-mediated activation of MAPK and PI3K signaling. We targeted these defective mechanotransduction mechanisms pharmacologically in both rasa1a and ephb4a mutant models, successfully reestablishing the fusion and constriction processes in preexisting malformations. This work identifies molecular actors of the flow-mediated blood vessel fusion mechanism, a specific angiogenetic program, and provides ground for treating VGAM and other vascular remodeling disorders.