# Endothelial RASOpathies and Vascular Malformations > **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $729,165 ## Abstract SUMMARY RAS signaling has been implicated in a wide spectrum of processes central to normal development and disease. Human mutations in RASA1 (a GAP negative regulator of RAS) are associated with capillary malformation-arteriovenous malformations (CM-AVM). These comprise a group of non-cancerous vascular lesions characterized by hyperproliferative endothelial cells that form abnormal and fragile blood vessels. CM- AVMs are underdiagnosed, but when identified in the clinic are often responsible for seizures, internal hemorrhage, and/or stroke. Germline mutations affecting one RASA1 allele alone are insufficient to give rise to vascular anomalies. For pathologic malformations to arise, additional somatic mutations are necessary. 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 additional altered genes collaborate with RASA1 mutations to facilitate the emergence of abnormal vessels? Answers to these questions are needed to develop pharmacological interventions and to develop strategies to restore vascular homeostasis. Here we will use novel mouse models that reproduce AVMs in several 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 RASA1-haploinsufficiency in mice provides a sensitized genetic platform that can be used to interrogate the effect of potential second-hit targets. Genetic combinatorial effects can be tested, followed, and studied in a highly tractable murine ear assay. Based on our preliminary data, 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 identify partners that synergize with RASA1 haploinsufficiency to promote the emergence of vascular malformations and, (2) To elucidate molecular targets that act downstream of RASA1 to promote junctional complex integrity and resist emergence of vascular anomalies. Mechanistic experiments will be performed with human cells and several mouse models. In addition, we will extend validation to human lesions through retrospective analysis of donor tissue. 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 complications from AVMs. The proposed studies will be directly applicable to the clinical setting of RAS- related malformations, as they will broaden our understanding of the disease and potentially aid in stratifying patients toward specific management paradigms. ## Key facts - **NIH application ID:** 10954082 - **Project number:** 1R01HL175575-01 - **Recipient organization:** NORTHWESTERN UNIVERSITY - **Principal Investigator:** M. LUISA IRUELA-ARISPE - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $729,165 - **Award type:** 1 - **Project period:** 2024-09-01 → 2028-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10954082 ## Citation > US National Institutes of Health, RePORTER application 10954082, Endothelial RASOpathies and Vascular Malformations (1R01HL175575-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10954082. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*