Endothelium‐derived lactate is required for pericyte function and blood–brain barrier maintenance. (3rd March 2022)

• Record Type: Journal Article
• Authors: Lee, Heon‐Woo; Xu, Yanying; Zhu, Xiaolong; Jang, Cholsoon; Choi, Woosoung; Bae, Hosung; Wang, Weiwei; He, Liqun; Jin, Suk‐Won; Arany, Zoltan; Simons, Michael
• Is Part Of: EMBO journal. Volume 41:Number 9(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-03
• Subjects: BBB permeability -- endothelial metabolism -- Glucose -- lactate -- pericyte metabolism; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021109890
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium‐derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial–pericyte proximity is required to facilitate the transport of endothelium‐derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter‐1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood–brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood–brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients. Synopsis: The contribution of circulating nutrients and metabolic pathways to crosstalk between endothelial cells and neurovascular pericytes remains ill‐defined. Here, lactate secreted by endothelial cells is identified as a principle source of carbons fueling pericyte metabolism and maintaining blood‐brain barrier integrity. Endothelium‐derived lactate is utilized for energy production and amino acid synthesis by pericytes in the CNS vasculature in mice. Loss of GLUT1 in endothelial cells reduces lactate secretion and pericyte coverage, increasing blood brain barrier permeability. MCT5 and MCT12 are lactate transporters responsible for shuttling lactate between endothelial cells and pericytes. Abstract : Metabolic shuttling of lactate between endothelial cells and neurovascular pericytes supports CNS vasculature integrity.