Association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α, endothelin-1 and inducible nitric oxide synthase in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension
WANG Jian-Rong, ZHOU Ying, SANG Kui, LI Ming-Xia
Department of Neonatology, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China. limingxia1203@sohu.com
Abstract OBJECTIVE: To investigate the association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α (HIF-1α), endothelin-1 (ET-1) and inducible nitric oxide synthase (iNOS) in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension (HPH). METHODS: A neonatal rat model of HPH was established as an HPH group, and normal neonatal rats were enrolled as a control group. The mean pulmonary arterial pressure (mPAP) was measured. The percentage of medial thickness to outer diameter of the small pulmonary arteries (MT%) and the percentage of medial cross-section area to total cross-section area of the pulmonary small arteries (MA%) were measured as the indicators for pulmonary vascular remodeling. The immunohistochemical reaction intensities for HIF-1α, ET-1 and iNOS and their mRNA expression in lung tissues of neonatal rats were measured. Correlation analysis was performed to determine the relationship between pulmonary vascular remodeling and mRNA expression of HIF-1α, ET-1 and iNOS. RESULTS: The mPAP of the HPH group kept increasing on days 3, 5, 7, 10, 14, and 21 of hypoxia, with a significant difference compared with the control group (P<0.05). The HPH group had significantly higher MT% and MA% than the control group from day 7 of hypoxia (P<0.05). HIF-1α protein expression increased significantly on days 3, 5, 7 and 10 days of hypoxia, and HIF-1α mRNA expression increased significantly on days 3, 5 and 7 days of hypoxia in the HPH group compared with the control group (P<0.05). ET-1 protein expression increased significantly on days 3, 5 and 7 days of hypoxia and ET-1 mRNA expression increased significantly on day 3 of hypoxia in the HPH group compared with the control group (P<0.05). Both iNOS protein and mRNA expression were significantly higher on days 3, 5 and 7 days of hypoxia than the control group (P<0.05). Both MT% and MA% were positively correlated with HIF-1α mRNA expression (r=0.835 and 0.850 repectively; P<0.05). CONCLUSIONS: Pulmonary vascular remodeling is developed on day 7 of hypoxia in neonatal rats. HIF-1α, ET-1 and iNOS are all involved in the occurrence and development of HPH in neonatal rats.
WANG Jian-Rong,ZHOU Ying,SANG Kui et al. Association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α, endothelin-1 and inducible nitric oxide synthase in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension[J]. CJCP, 2013, 15(2): 138-144.
WANG Jian-Rong,ZHOU Ying,SANG Kui et al. Association between pulmonary vascular remodeling and expression of hypoxia-inducible factor-1α, endothelin-1 and inducible nitric oxide synthase in pulmonary vessels in neonatal rats with hypoxic pulmonary hypertension[J]. CJCP, 2013, 15(2): 138-144.
［1］He ZH, Dai AG, Zhang XF, Tan XW. Expression of hypoxia inducible factor-1 alpha and inducible nitric oxide synthase gene in the development of hypoxic pulmonary hypertension in rats［J］. Clin Rehab Tissue Eng Res, 2007, 11(36): 7290-7294.
［2］Budhiraja R, Tuder RM, Hassoun PM. Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension［J］. Circulation, 2005, 12(4): 159-165.
［6］Li QF, Dai AG. Hypoxiainducible factor1alpha regulates the role of vascular endothelial growth factor on pulmonary arteries of rats with hypoxia induced pulmonary hypertension［J］. Chin Med J(Engl), 2004, 117(6): 1023-1028.
［7］Schultz K, Fanburg BL, Beasley D. Hypoxia and hypoxia-inducible factor-1alpha promote growth factor-induced proliferation of human vascular smooth muscle cells［J］. Am J Physiol, 2006, 290(6): H2528-H2534.
［8］Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1［J］. Blood, 2005, 105(2): 659-669.
［13］Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine ［J］. Nature, 1980, 288(5789): 373-376.
