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bioRxiv · 10.1101/2021.07.21.453236

Venous activation of MEK/ERK drives development of arteriovenous malformation and blood 2 flow anomalies with loss of Rasa1

Greysson-Wong, J.·Rode, R.·Ryu, J.-R.·Rinker, K. D.·Childs, S. J.
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Abstract

Vascular malformations develop when growth pathway signaling goes awry in the endothelial cells lining blood vessels. Arteriovenous malformations (AVMs) arise where arteries and veins abnormally connect in patients with loss of RASA1, a Ras GTPase activating protein, and, as we show here, in zebrafish rasa1 mutants. Mutant fish develop massively enlarged vessels at the connection between artery and vein in the tail vascular plexus. These AVMs progressively enlarge and become filled with slow-flowing blood and have a greater drop in pulsatility from the artery to the vein. Expression of the flow responsive transcription factor klf2a is diminished in rasa1 mutants, suggesting changes in flow velocity and pattern contribute to the progression of vessel malformations. Migration of endothelial cells is not affected in rasa1 mutants, nor is cell death or proliferation. Early developmental artery-vein patterning is also normal in rasa1 mutants, but we find that MEK/ERK signaling is ectopically activated in the vein as compared to high arterial activation seen in wildtype animals. MEK/ERK signaling inhibition prevents AVM development of rasa1 mutants, demonstrating venous MEK/ERK drives the initiation of rasa1 AVMs. Thus, rasa1 mutants show overactivation of MEK/ERK signaling causes AVM formation, altered blood flow and downstream flow responsive signaling. SummaryThe zebrafish model of RASA1 capillary malformation and arteriovenous malformation (CM-AVM1) develops cavernous vascular malformations driven by ectopic MEK/ERK signaling in the vein, disrupting flow and downstream mechanosensitive signaling.

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Greysson-Wong, J., Rode, R., Ryu, J.-R., Rinker, K. D., Childs, S. J.. 2021-07-21. Venous activation of MEK/ERK drives development of arteriovenous malformation and blood 2 flow anomalies with loss of Rasa1. https://doi.org/10.1101/2021.07.21.453236

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