Friday, May 9, 2025
5/9/2025
Venous Malformations (VM): A Murine Mdoel to Identify Therapies to Target Aberrant Venous Development - PROJECT SUMMARY/ ABSTRACT: Venous malformations (VM) originate from impaired development of the venous network, resulting in massively dilated and dysfunctional veins. Vascular lesions are usually present at birth, continuing to expand with time and never spontaneously regress. VM result in significant morbidity and pain often leading to serious local and systemic complications. Standard clinical management consists of sclerotherapy and surgical resection. However, because these therapies manage symptoms rather than targeting underlying disease etiology, malformed veins often require repeated interventions. Therefore, novel targeted therapies for VM are of high importance. Gain-of function mutations in the endothelial-specific tyrosine kinase receptor TIE2 have been identified as the leading driver of VM. TIE2 has been shown to regulate both maintenance of vascular quiescence and promotion of angiogenesis, but its role in the vascular lumen expansion has not been explored. Research into the molecular and cellular abnormalities which result from hyperactive TIE2 will provide the necessary groundwork for the development of the targeted molecular treatments for VM. Our results, recently published, show that TIE2 signaling promotes activation of c-ABL (Abelson kinase 1) and that genetic and pharmacological c-ABL targeting significantly reduced vascular lumen size. The mechanisms leading to the pathogenic lumen expansion are still largely unexplored and the role of c-ABL in the pathophysiology of VM and vascular anomalies is unknown. With the identification of novel mediators of the TIE2-c-ABL signaling axis, we can now develop a research program to investigate their role in vascular lumen expansion with the goal of identifying novel targets for VM. To perform these studies, we will utilize our VM xenograft murine models and a recently devised in vitro three- dimensional system to study VM lumen formation and expansion. To advance our understanding of VM, we will employ a rigorous approach based on the complementary use of the well-established HUVEC-TIE2-L914F cell line, VM patient derived EC and patient tissue to confirm the significance of our findings for the pathophysiology of VM. Additionally, our studies on VM will provide cellular and mechanistic insights to advance our understanding of pathological and physiological vessel formation and size maintenance.
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