Hypoxia Inhibits Cell Cycle Progression and Cell Proliferation in Brain Microvascular Endothelial Cells via the miR-212-3p/MCM2 Axis

Hypoxia impairs blood-brain barrier (BBB) structure and function, causing pathophysiological changes in the context of stroke and high-altitude brain edema. Brain microvascular endothelial cells (BMECs) are major structural and functional elements of the BBB, and their exact role in hypoxia remains unknown. Here, we first deciphered the molecular events that occur in BMECs under 24 h hypoxia by whole-transcriptome sequencing assay. We found that hypoxia inhibited BMEC cell cycle progression and proliferation and downregulated minichromosome maintenance complex component 2 (Mcm2) expression. Mcm2 overexpression attenuated the inhibition of cell cycle progression and proliferation caused by hypoxia. Then, we predicted the upstream miRNAs of MCM2 through TargetScan and miRanDa and selected miR-212-3p, whose expression was significantly increased under hypoxia. Moreover, the miR-212-3p inhibitor attenuated the inhibition of cell cycle progression and cell proliferation caused by hypoxia by regulating MCM2. Taken together, these results suggest that the miR-212-3p/MCM2 axis plays an important role in BMECs under hypoxia and provide a potential target for the treatment of BBB disorder-related cerebrovascular disease.

Automated summary

Hypoxia impairs the structure and function of the blood-brain barrier (BBB), leading to pathophysiological changes in stroke and high-altitude brain edema. Brain microvascular endothelial cells (BMECs) are important elements of the BBB, but their role in hypoxia is still unknown. This study found that hypoxia inhibits BMEC cell cycle progression and proliferation, and downregulates the expression of minichromosome maintenance complex component 2 (Mcm2). Overexpression of Mcm2 attenuates the inhibitory effects of hypoxia on cell cycle progression and proliferation. The miRNA miR-212-3p is identified as an important regulator of Mcm2 in hypoxia, and its inhibition can rescue the effects of hypoxia on BMECs.