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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) \u2013 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.<\/jats:p>","DOI":"10.1242\/dev.201820","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T13:15:55Z","timestamp":1694697355000},"source":"Crossref","is-referenced-by-count":16,"title":["<i>rasa1<\/i>\n                    -related arteriovenous malformation is driven by aberrant venous signalling"],"prefix":"10.1242","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6097-3013","authenticated-orcid":false,"given":"Jasper","family":"Greysson-Wong","sequence":"first","affiliation":[{"name":"Alberta Children's Hospital Research Institute, University of Calgary 1 , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"},{"name":"University of Calgary 2 Department of Biochemistry and Molecular Biology , , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Rode","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute, University of Calgary 1 , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"},{"name":"University of Calgary 3 Department of Chemical and Petroleum Engineering , , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4080-9280","authenticated-orcid":false,"given":"Jae-Ryeon","family":"Ryu","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute, University of Calgary 1 , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"},{"name":"University of Calgary 2 Department of Biochemistry and Molecular Biology , , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo Li","family":"Chan","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute, University of Calgary 1 , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"},{"name":"University of Calgary 2 Department of Biochemistry and Molecular Biology , , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paniz","family":"Davari","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute, University of Calgary 1 , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"},{"name":"University of Calgary 2 Department of Biochemistry and Molecular Biology , , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8827-8693","authenticated-orcid":false,"given":"Kristina D.","family":"Rinker","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute, University of Calgary 1 , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"},{"name":"University of Calgary 3 Department of Chemical and Petroleum Engineering , , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2261-580X","authenticated-orcid":false,"given":"Sarah J.","family":"Childs","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute, University of Calgary 1 , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"},{"name":"University of Calgary 2 Department of Biochemistry and Molecular Biology , , 3330 University Drive NW, Calgary, AB T2N 4N1 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"2023091417152357600_DEV201820C1","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1172\/JCI98589","article-title":"Mosaic RAS\/MAPK variants cause sporadic vascular malformations which respond to targeted therapy","volume":"128","author":"Al-Olabi","year":"2018","journal-title":"J. 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