Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis

Balkrishna Chaube, Kathryn M. Citrin, Mahnaz Sahraei, Abhishek K. Singh, Diego Saenz Urturi, Wen Ding, Richard W. Pierce, Raaisa Raaisa, Rebecca Cardone, Richard Kibbey, Carlos Fernández-Hernando and Yajaira Suárez ()
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Balkrishna Chaube: Yale University School of Medicine
Kathryn M. Citrin: Yale University School of Medicine
Mahnaz Sahraei: Yale University School of Medicine
Abhishek K. Singh: Yale University School of Medicine
Diego Saenz Urturi: Yale University School of Medicine
Wen Ding: Yale University School of Medicine
Richard W. Pierce: Yale University School of Medicine
Raaisa Raaisa: Yale University
Rebecca Cardone: Yale University
Richard Kibbey: Yale University School of Medicine
Carlos Fernández-Hernando: Yale University School of Medicine
Yajaira Suárez: Yale University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Angiopoietin-like 4 (ANGPTL4) is known to regulate various cellular and systemic functions. However, its cell-specific role in endothelial cells (ECs) function and metabolic homeostasis remains to be elucidated. Here, using endothelial-specific Angptl4 knock-out mice (Angptl4iΔEC), and transcriptomics and metabolic flux analysis, we demonstrate that ANGPTL4 is required for maintaining EC metabolic function vital for vascular permeability and angiogenesis. Knockdown of ANGPTL4 in ECs promotes lipase-mediated lipoprotein lipolysis, which results in increased fatty acid (FA) uptake and oxidation. This is also paralleled by a decrease in proper glucose utilization for angiogenic activation of ECs. Mice with endothelial-specific deletion of Angptl4 showed decreased pathological neovascularization with stable vessel structures characterized by increased pericyte coverage and reduced permeability. Together, our study denotes the role of endothelial-ANGPTL4 in regulating cellular metabolism and angiogenic functions of EC.

Date: 2023
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DOI: 10.1038/s41467-023-43900-0

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