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

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 () and Masuko Ushio-Fukai ()
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Dipankar Ash: Medical College of Georgia at Augusta University
Varadarajan Sudhahar: Medical College of Georgia at Augusta University
Seock-Won Youn: Medical College of Georgia at Augusta University
Mustafa Nazir Okur: National Institutes of Health
Archita Das: Medical College of Georgia at Augusta University
John P. O’Bryan: Medical University of South Carolina
Maggie McMenamin: Medical College of Georgia at Augusta University
Yali Hou: Medical College of Georgia at Augusta University
Jack H. Kaplan: University of Illinois College of Medicine
Tohru Fukai: Medical College of Georgia at Augusta University
Masuko Ushio-Fukai: Medical College of Georgia at Augusta University

Nature Communications, 2021, vol. 12, issue 1, 1-16

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

Date: 2021
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DOI: 10.1038/s41467-021-23408-1

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