Developmental vascular malformations in EPAS1 gain-of-function syndrome.

Area of Science:

• Genetics
• Vascular Biology
• Oncology

Background:

• Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), are linked to paraganglioma, somatostatinoma, and polycythemia.
• HIF-2α is an angiogenic transcription factor when dimerized with HIF-1β.

Purpose of the Study:

• To investigate vascular malformations in patients and a mouse model with EPAS1 gain-of-function mutations.
• To identify new clinical features associated with EPAS1 gain-of-function syndrome.

Main Methods:

• Evaluated patients with paraganglioma/pheochromocytoma for EPAS1 mutations and vascular malformations.
• Utilized intravital 2-photon microscopy, Microfil perfusion, 14T MRI, micro-CT, and histology in Epas1A529V mutant mice.
• Examined retinal and dural vasculature in mice at various developmental stages using immunofluorescence and confocal imaging.

Main Results:

• A spectrum of vascular malformations was identified in all 9 syndromic patients and all tested mutant mice.
• Patient vessels showed higher variant allele frequency than adjacent normal tissue.
• Retinal and intracranial dural veins in mutant mice exhibited abnormal regression during development.

Conclusions:

• Vascular malformation is a newly identified clinical feature of EPAS1 gain-of-function syndrome.
• These findings expand the understanding of EPAS1-related disorders and their phenotypic spectrum.