Role of hypoxia-inducible factor-1α in hypoxia-induced pulmonary hypertension of neonatal rats and its association with pulmonary vascular remodeling / 中华围产医学杂志

ABSTRACT

Objective To investigate the serum concentration and the lung tissue expression level of hypoxia-inducible factor-1α (HIF-1α) in neonatal rats with hypoxia-induced pulmonary hypertension (HPH),and the role of HIF-1α in pathogenesis of HPH and pulmonary vascular remodeling.Methods Eighty neonatal Wistar rats were randomly assigned into normoxia and hypoxic group,forty in each group.HPH models were established on rats in hypoxic group.On the 3rd,7th,14th and 21st day after modeling,ten rats in each group were taken to measure the mean pulmonary arterial pressure (mPAP).Meanwhile,serum HIF-1α concentration were determined by enzyme-linked immunosorbent assay,while expression of HIF-1α in lung tissue were detected by immunohistochemistry and real time polymerase chain reaction.After hematoxylineosin and Van Gieson staining,morphological changes of pulmonary arterioles of rats in both groups were observed by optical microscope.Intima-media thickness/external diameter ratio (MT) and medial wall cross sectional area/vessel total cross-sectional area ratio (MA) were determined.Wilcoxon rank sum test,t-test,Ridit analysis,Pearson correlation and Spearman rank correlation test were applied for statistical analysis.Results mPAP in both groups kept increasing as the time went on.mPAP in hypoxic group were higher than that innormoxiagroup[(8.59±1.57) mmHgvs (6.14±1.02) mmHg,(11.63±2.56) mmHgvs (8.33±0.76) mmHg,(15.29±2.88) mmHgvs (10.92±2.74) mmHgand (18.04±2.69) mmHgvs (12.17±1.64) mmHg on the 3rd,7th,14th and 21st day after hypoxia modeling (t=4.14,3.91,3.48 and 5.89,all P＜0.05).Serum concentration,expressions of mRNA and immune response intensity of HIF-1α in hypoxic group were higher than those in normoxia group on the 3rd,7th and 14th day after hypoxia [serum concentration(805.67±19.52) μg/molvs (204.34±83.21) μg/mol,(906.29±24.24) μg/molvs (548.93±11.78) μg/mol and (939.25±28.57) μg/mol vs (674.44± 17.41) μg/mol,t=6.43,4.11 and 2.34,respectively,all P＜0.05; relative expressions of HIF-1α mRNA0.98±0.35 vs 0.23±0.16,1.30±0.49 vs 0.69±0.13 and 1.45±0.76 vs 0.64±0.21,respectively,t=4.56,2.72 and 4.63,all P＜0.05; immune response intensity of HIF-1α (average Ridit value)0.318 vs 0.183,0.303 vs 0.198 and 0.374 vs 0.176,respectively,u=3.26,2.73 and 3.91,all P＜0.05].MT and MA in hypoxic group were higher than those in normoxia group [MT52.71％ (45.91％-63.23％) vs 47.42％ (41.14％ 56.17％),61.28％ (52.25％-68.63％) vs 50.22％(43.79％ 58.40％) and 65.24％ (56.02％-71.28％) vs 53.78％ (48.02％-64.58％) at 7,14 and 21st day respectively,u=2.08,4.54 and 4.37; MA60.89％ (54.04％ 66.21％) vs 55.19％ (50.32％-63.59％),66.09％ (58.52％-72.58％) vs 59.77％ (53.55％-67.09％) and 68.25％(62.02％-74.51％)vs 61.40％(50.74％-70.55％),respectively,u=2.16,2.27 and 3.18,all P＜0.05].There were positive relations between HIF-1α and mPAP (r=0.294),as well as MT and MA (r=0.548 and 0.265,all P＜0.05).Conclusions HIF-1α may play a role in the pathogenesis of HPH.Pulmonary vascular remodeling occurred after seven days of hypoxia induction and may be exacerbated as the hypoxic time is prolonged,which might be prevented with early interventions.