The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2

• DOI: 10.1038/s41467-021-23408-1
• Publication Date: 2021-05-25T10:02:59Z
• Authors: Dipankar Ash; Varadarajan Sudhahar; Seock-Won Youn; Mustafa Nazir Okur; Archita Das; John P. O’Bryan; Maggie McMenamin; Yali Hou; Jack H. Kaplan; Tohru Fukai; Masuko Ushio-Fukai
• Keywords: ATP7A; Limiting; Degradation

VEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) plays a central role angiogenesis. The P-type ATPase transporter ATP7A regulates copper homeostasis, and its angiogenesis is entirely unknown. Here, we describe the unexpected crosstalk between Copper ATP7A, autophagy, degradation. functional significance of this was demonstrated by finding that inducible EC-specific deficient mice or ATP7A-dysfunctional ATP7Amut showed impaired post-ischemic neovascularization. In ECs, loss inhibited VEGF-induced angiogenic responses, part promoting ligand-induced protein Mechanistically, VEGF stimulated translocation from trans-Golgi network to plasma membrane where it bound VEGFR2, which prevented autophagy-mediated lysosomal degradation inhibiting autophagic cargo/adapter p62/SQSTM1 binding ubiquitinated VEGFR2. Enhanced autophagy flux due dysfunction vivo confirmed reporter CAG-ATP7Amut -RFP-EGFP-LC3 transgenic mice. summary, our study uncovers novel function limit thereby angiogenesis, restores perfusion recovery Thus, identified as potential therapeutic target for treatment ischemic cardiovascular diseases.