PUBLICATION
rasa1-related arteriovenous malformation is driven by aberrant venous signalling
- Authors
- Greysson-Wong, J., Rode, R., Ryu, J.R., Chan, J.L., Davari, P., Rinker, K.D., Childs, S.J.
- ID
- ZDB-PUB-230915-53
- Date
- 2023
- Source
- Development (Cambridge, England) 150(18): (Journal)
- Registered Authors
- Childs, Sarah J.
- Keywords
- Arteriovenous malformation, Blood vessel, MAPK, RASA1
- MeSH Terms
-
- Animals
- Arteriovenous Malformations*/genetics
- GTPase-Activating Proteins
- Humans
- Mitogen-Activated Protein Kinase Kinases
- Veins
- Zebrafish*
- p120 GTPase Activating Protein/genetics
- PubMed
- 37708300 Full text @ Development
Citation
Greysson-Wong, J., Rode, R., Ryu, J.R., Chan, J.L., Davari, P., Rinker, K.D., Childs, S.J. (2023) rasa1-related arteriovenous malformation is driven by aberrant venous signalling. Development (Cambridge, England). 150(18):.
Abstract
Arteriovenous malformations (AVMs) develop where abnormal endothelial signalling allows direct connections between arteries and veins. Mutations in RASA1, a Ras GTPase activating protein, lead to AVMs in humans and, as we show, in zebrafish rasa1 mutants. rasa1 mutants develop cavernous AVMs that subsume part of the dorsal aorta and multiple veins in the caudal venous plexus (CVP) - a venous vascular bed. The AVMs progressively enlarge and fill with slow-flowing blood. We show that the AVM results in both higher minimum and maximum flow velocities, resulting in increased pulsatility in the aorta and decreased pulsatility in the vein. These hemodynamic changes correlate with reduced expression of the flow-responsive transcription factor klf2a. Remodelling of the CVP is impaired with an excess of intraluminal pillars, which is a sign of incomplete intussusceptive angiogenesis. Mechanistically, we show that the AVM arises from ectopic activation of MEK/ERK in the vein of rasa1 mutants, and that cell size is also increased in the vein. Blocking MEK/ERK signalling prevents AVM initiation in mutants. Alterations in venous MEK/ERK therefore drive the initiation of rasa1 AVMs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping