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

Author:

Chaube BalkrishnaORCID,Citrin Kathryn M.,Sahraei Mahnaz,Singh Abhishek K.,de Urturi Diego Saenz,Ding Wen,Pierce Richard W.ORCID,Raaisa Raaisa,Cardone Rebecca,Kibbey Richard,Fernández-Hernando CarlosORCID,Suárez YajairaORCID

Abstract

AbstractAngiopoietin-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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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