Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China.
EMBO J. 2022 May 2;41(9):e109890. doi: 10.15252/embj.2021109890. Epub 2022 Mar 3.
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.
内皮细胞与负责形成血管壁的其他细胞类型不同，它们非常依赖糖酵解来满足大部分能量需求，从而导致大量乳酸的产生。我们发现内皮细胞衍生的乳酸被周细胞摄取，并为周细胞代谢做出重要贡献，包括能量生成和氨基酸合成。内皮细胞和周细胞之间的接近程度对于促进内皮细胞衍生的乳酸进入周细胞的运输是必需的。通过在小鼠中敲除葡萄糖转运蛋白-1（GLUT1）来抑制内皮细胞中的乳酸生成，会导致视网膜和脑血管中的周细胞覆盖丢失，从而导致血脑屏障破裂和通透性增加。通过口服补充乳酸，这些异常可以得到很大程度的恢复。我们的研究表明内皮细胞和周细胞代谢之间存在意想不到的联系，以及内皮细胞乳酸生成在维持血脑屏障完整性方面的作用。此外，我们的观察表明，补充乳酸可能是治疗 GLUT1 缺乏代谢综合征患者的一种有效方法。
