Arterial-Lymphatic-Like Endothelial Cells Appear in Hereditary Hemorrhagic Telangiectasia 2 and Contribute to Vascular Leakage and Arteriovenous Malformations

• DOI: 10.1161/circulationaha.124.070925
• Publication Date: 2024-10-21T09:01:03Z
• Authors: Yang Yang; Xiuju Wu; Yan Zhao; Daoqin Zhang; Li Zhang; Xinjiang Cai; Jaden Ji; Zheng Jing; Kristina I. Boström; Yucheng Yao
• Keywords: Lymphatic Endothelium; Lymphatic vessel

BACKGROUND: Arteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia. Loss-of-function mutations in the activin receptor‐like kinase 1 ( Alk1 ) linked to telangiectasia type 2. METHODS: Endothelial-specific deletion Alk1, endothelial lineage tracing, transcriptomics single-cell analysis, and electron microscopy were performed examine vascular phenotype characteristics ALK1-deficient cells (ECs) after EC-specific deletion. Ischemia assays used cell capacity for malformation. Connectivity Map with transcriptomic analysis was applied identify chemical compounds. Specific methods arteriovenous malformations, such as micro–computed tomography, other molecular biological tools also performed. RESULTS: We endothelial-specific mice found severe leakage. The revealed a new distinctive cluster formed where coexpressed arterial lymphatic markers. projected that these potentially originated from ECs This population referred arterial-lymphatic-like according its cellular markers, appearance validated pulmonary small arteries Transplantation caused malformations. Endothelial tracing confirmed derived ALK1 depleted ECs, ECs. discovered SOX17 (SRY-box transcription factor 17) induction responsible derivation showed direct binding MDM2 (mouse double minute 2) required Sox17 execute this activity. Inhibition reduced mouse model. CONCLUSIONS: Together, our studies mechanistic underpinnings signaling regulating provided possibilities therapeutic strategies