Endothelial destabilizing mutations that drive vascular malformations

Project: Research project

Project Details


Mutations in RASA1, a gene that encodes for the Ras GTPase-activating protein 1, have been previously associated with capillary malformation-arteriovenous malformation syndrome (CM-AVM). These vascular anomalies are characterized by multi-focal lesions that can affect several organs including the brain and result in life-threatening hemorrhage, strokes and / or seizures. Importantly germline mutations in RASA1 affect one allele and alone do not result in abnormalities, for this additional somatic mutation(s) (“second hit”) are necessary. Open questions in the field are: What are the collaborative pathways that, when affected, trigger malformations? and How do they work together to facilitate the emergence of abnormal vessels? Answers to these questions are needed for the identification of potential targets and the development of approaches to correct these vascular anomalies. Our preliminary in vivo data shows a mouse model that reproduces AVMs in multiple organs, and our in vitro data has uncovered novel functions of RASA1 as a critical regulator of endothelial cell-cell junctions, which control vascular integrity. In addition, we have created a novel in vivo platform to test potential candidates for somatic second-hit mutations and explore the combinatorial effect of these mutations in the mouse ear. Based on our preliminary data and in light of the gaps in existing knowledge in the vascular biology field, we hypothesize that RASA1 loss of heterozygosity (LOH) alters junctional complexes sensitizing endothelial cells to proliferative pathways and the emergence of vascular malformations. Two aims were developed to test this hypothesis, (1) to elucidate the molecular deficiencies downstream RASA1 that result in vascular anomalies. And (2) to identify partners that synergize with RASA1 haploinsufficiency to promote the emergence of vascular malformations. Clarifying the contribution of RASA1 to vascular homeostasis could offer an unprecedented opportunity for intervention. In addition, understanding cooperating genes will improve screening protocols and benefit patients harboring RASA1 mutations with the risk of developing life-threatening complications from AVMs.
Effective start/end date1/1/2312/31/24


  • American Heart Association (1022462)


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