[Hypoxia-inducible factor 1alpha regulates vascular endothelial growth factor's roles on pulmonary arteries of rats with hypoxia-induced pulmonary hypertension].
OBJECTIVE
To investigate the dynamic expression of hypoxia inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension.


METHODS
Forty male adult Wistar rats were randomly divided into five groups: a control group (C group) and groups with hypoxia for 3, 7, 14 and 21 days (H(3), H(7), H(14) and H(21) group), eight rats per group. Mean pulmonary pressure (mPAP), vessel morphometry and right ventricle hypertrophy index (RVHI) were measured. Lungs were inflation fixed for in situ hybridization and immunohistochemistry.


RESULTS
mPAP increased significantly after 7-day of hypoxia [(18.41 +/- 0.37) mm Hg, P < 0.05], reaching its peak after 14-day of hypoxia, then remained on the high level. Pulmonary artery remodeling index (outer diameter 100 - 150 micro m) and RVHI became evident after 14-day of hypoxia. Expression of HIF-1alpha protein in control group was poorly positive, but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats. In pulmonary arterial tunica media, the levels of HIF-1alpha protein was markedly up-regulated after 3-day (0.178 +/- 0.017, P < 0.05), reaching its peak after 7-day of hypoxia (0.221 +/- 0.021, P < 0.05), then tended to decline after 14-day and 21-day of hypoxia. HIF-1alpha mRNA staining was poorly positive in control, hypoxia for 3 days and hypoxia for 7 days, but began to increase significantly after 14-day of hypoxia (0.203 +/- 0.024, P < 0.05), then remained stable. Expression of VEGF protein began to increase after 7-day of hypoxia (0.074 +/- 0.022, P < 0.05), reaching its peak after 14-day of hypoxia (0.147 +/- 0.017, P < 0.05), then remained on the high level. VEGF mRNA in control and hypoxia for 3 days was poorly positive, but began to increase after 7-day of hypoxia (0.138 +/- 0.010, P < 0.05), and remained on the high level thereafter. VEGF mRNA located mainly in tunica intima and tunica media, whereas VEGF protein located predominantly in tunica intima. Linear correlation analysis showed that HIF-1alpha mRNA, VEGF, and mPAP were correlated with vessel morphometry and RVHI (P < 0.01). HIF-1alpha protein (tunica intima) was positively correlated with VEGF mRNA and protein (P < 0.01).


CONCLUSIONS
HIF-1alpha and VEGF are both involved in the pathogenesis of hypoxia-induced pulmonary hypertension in rats. HIF-1alpha protein may regulate the expression of VEGF gene by transcriptional activation, resulting in the occurrence and development of hypoxic pulmonary hypertension.
Li
Qi-fang
QF
Department of Respiratory Disease Research, Hunan Institute of Gerontology, Hunan Geriatric Hospital, Changsha 410001, China.
Dai
Ai-guo
AG
D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A