Developmental vascular malformations in EPAS1 gain-of-function syndrome

• Published in: JCI insight Vol. 6; no. 5
• Main Authors: Rosenblum, Jared S, Wang, Herui, Dmitriev, Pauline M, Cappadona, Anthony J, Mastorakos, Panagiotis, Xu, Chen, Jha, Abhishek, Edwards, Nancy, Donahue, Danielle R, Munasinghe, Jeeva, Nazari, Matthew A, Knutsen, Russell H, Rosenblum, Bruce R, Smirniotopoulos, James G, Pappo, Alberto, Spetzler, Robert F, Vortmeyer, Alexander, Gilbert, Mark R, McGavern, Dorian B, Chew, Emily, Kozel, Beth A, Heiss, John D, Zhuang, Zhengping, Pacak, Karel
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 08.03.2021; American Society for Clinical investigation
• Subjects: Adolescent; Adult; Angiogenesis; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Development; Female; Gain of Function Mutation; Gene Expression Regulation; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Neuroendocrine Tumors - genetics; Polycythemia - genetics; Vascular Malformations - genetics; Young Adult; Development; Angiogenesis; Genetic diseases; Mouse models
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.144368

Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.