[Regulatory role of hypoxia inducible factor-1 alpha in the changes of contraction of vascular smooth muscle cell induced by hypoxia].
OBJECTIVE
To observe the regulatory role and mechanism of hypoxia inducible factor-1 alpha (HIF-1 alpha) in the contractile changes of vascular smooth muscle cell (VSMC) induced by hypoxia.


METHODS
Cells were divided into three groups: normal, hypoxia and oligomycin treated groups. VSMC and vascular endothelial cell (VEC) were co-cultured in Transwell models with the hypoxic time of 0, 0.5, 1, 2, 3, 4 and 6 hours respectively. The contractile response of VSMC to norepinephrine were determined by measuring the fluorescent infiltration rate in the lower chamber. The mRNA expression of HIF-1 alpha, endothelial-nitric oxide synthase (eNOS), inducible-nitric oxide synthase(iNOS), heme oxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) were determined by reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
VSMC contraction was increased at the early stage of hypoxia with the 1.53-fold increase at 0.5 hour as compared to the normal group (P<0 .01), and decreased gradually at the prolonged period of hypoxia with the drop of 30% at 6 hours as compared to the normal group (P<0.05). Oligomycin treatment significantly inhibited the increase of VSMC contraction at early stage, while improved it at late hypoxic period with the 6 hours increase of 12.8% (P<0.05). HIF-1 alpha, iNOS, COX-2 and HO-1 mRNA exhibited a time-dependent increase following hypoxia, and peaked at 6, 2, 3 and 4 hours respectively, they were increased 1.62, 3.23, 2.26 and 2.86-folds as compared with normal group (all P<0.01). iNOS, COX-2 and HO-1 mRNA expression were fluctuated in the normal range following oligomycin administration (all P>0.05).


CONCLUSIONS
Hypoxia can elicit a biphasic changes of VSMC contraction, and HIF-1 alpha seems to play an important role in the regulation of VSMC contraction induced by hypoxia by regulating eNOS, iNOS, COX-2 and HO-1 expression.
Zhang
Yuan
Y
State Key Laboratory of Trauma, Burns and Combined Injury, The Second Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, China.
Liu
Liang-ming
LM
Ming
Jia
J
Yang
Guang-ming
GM
Chen
Wei
W
D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014661:Vasoconstriction / Q000502:physiology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human