title: Nitric oxide from brain microvascular endothelial cells may initiate the compensatory response to mild hypoxia of astrocytes in a hypoxia-inducible factor-1α dependent manner.
abstract: The physiological level of nitric oxide (NO) released by brain microvascular endothelial cells (BMECs) at normoxia can block the degradation of hypoxia-inducible factor-1α (HIF-1α) in astrocytes and initiate the compensatory response to hypoxia. However, it is unclear whether this occurs at mild hypoxia. This study was to investigate the expression of HIF-1α, VEGF and LDHA and the lactic acid production in astrocytes with or without co-culture with BMECs after mild hypoxia exposure. During mild hypoxia (5% O2), exogenous NO blocked the degradation of HIF-1α in astrocytes but up-regulated the transcription of VEGF and LDHA, accompanied by elevated expression of VEGF protein and increased production of lactic acid. This was further confirmed by silencing of HIF-1α expression in astrocytes. In astrocytes co-cultured with primary rat BMEC under mild hypoxia, NO was released by the BMECs and prevented the degradation of HIF-1α in astrocytes, leading to the up-regulated mRNA expression of VEGF and LDHA, elevated VEGF protein expression and increased production of lactic acid. In BMECs, NO was derived from intracellular eNOS. Based on these findings, we hypothesize that, under mild hypoxia, even though astrocytes do not respond to hypoxia, NO produced by BMECs may transmit a hypoxia signal to astrocytes, triggering their adaptive response via HIF-1α.
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China.
authors.forename: Xinchuan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Clinical Laboratory Diagnostic Center, Urumqi General Hospital of Lanzhou Military Region Urumqi 830000, Xinjiang, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Fu
authors.affiliation: Medical Research Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
keywords: Brain microvascular endothelial cells; astrocytes; hypoxia; hypoxia-inducible factor-1α; nitric oxide