Development of Rasa1 arteriovenous malformations

Abstract

Precise regulation of signalling is critical to ensure proper formation of blood vessel networks during development. Mutations in key genes may disturb this finely tuned process, resulting in malformed vessels. Mutations in RASA1, a Ras GTPase activating protein, leads to the development of arteriovenous malformations (AVMs), where arteries are connected directly to veins without interceding capillary beds. Using zebrafish, I show that rasa1 mutants also develop AVMs in their tail vasculature, which subsume the posterior of the dorsal aorta and caudal venous plexus. The development of rasa1 AVMs does not depend on flow and modulating flow does not prevent or rescue AVM formation. However, blood flow slows in the cavernous AVM, changing flow-responsive signalling reducing expression of flow responsive transcription factor klf2a. Incomplete remodelling of the caudal venous plexus is visualized by an excess of residual intraluminal pillars, an indication of impaired intussusceptive angiogenesis. I show that AVM development is dependant on venous activation of MEK/ERK signalling and that inhibition of MEK signalling can prevent AVM development during an early developmental window, but MEK inhibition cannot rescue an AVM that has already formed. For the first time, I show that Bmp and Vegf signalling both play a role in AVM development, pathways that are important in other vascular malformations but had yet to be explored in RASA1 models.