Endothelial destabilizing mutations that drive vascular malformations.
Description: Mutations in RASA1, a gene that encodes Ras GTPase-activating protein 1, have been 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 affecting one allele (haploinsufficiency) do not result in overgrowth. For pathologies to arise, additional somatic mutations are necessary either in the second RASA1 allele, or in genes from complementing pathways. Open questions in the field include 1) What are the secondary hits that trigger malformations in the context of RASA1 haploinsufficiency and, 2) How do the collaborative pathways work with RASA1 mutations to facilitate the emergence of abnormal vessels? Answers to these questions are needed to evaluate potential targets and develop approaches to restore vascular homeostasis. We developed a mouse model that reproduces the AVMs in multiple organs to study the biological consequences of RASA1 loss. Preliminary experiments revealed that RASA1 is a critical regulator of endothelial cell-cell junctions and vascular integrity. In addition, we found that mice carrying one normal and one mutant copy of RASA1 provide a novel sensitized genetic platform useful to interrogate the role of candidate second-hit targets. These combinatorial effects can be tested using a highly accessible and tractable mouse ear assay. Based on our preliminary data and in light of gaps in existing knowledge in the vascular biology field, we hypothesize that RASA1 haploinsufficiency alters junctional complexes, and sensitizes endothelial cells to the emergence of vascular malformations. Two aims were developed to test this hypothesis: (1) To elucidate the molecular targets downstream of RASA1 that promote junctional complex integrity (and resist 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 by identifying the key players in this debilitating condition. In addition, understanding cooperating genes will improve screening protocols and benefit patients harboring RASA1 mutations who live with an elevated lifetime risk of developing life-threatening complications from AVMs.
Funder: American Heart Association
Amount: $147,300
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2023-04-01
End date: 2025-03-31
Investigators: ANA MOMPEON CAMPOS, ANA MOMPEON CAMPOS
Institution: Northwestern University - Chicago Campus
Funded outputs count: 2
Funder award ID: 23POST1022462
OpenAlex ID: G6067289919