The role of expression of transforming growth factor-β_1 and inducible nitric oxide synthase and pulmonary vascular myofibroblast formation in the hypoxic pulmonary vascular remodeling of rats

Objective To investigate the role of dynamic expression of transforming growth factor-β_1(TGF-β_1) and inducible nitric oxide synthase(iNOS) and myofibroblast formation in hypoxic pulmonary vascular remodeling of rats. Methods Forty male Wistar rats were exposed to hypoxia for 0, 3, 7, 14 days or 21 days. Mean pulmonary arterial pressure (mPAP), vessel morphometry, right ventricle hypertrophy index (RVHI) were measured. Lungs were fixed for in situ hybridization and immunohistochemistry. Ultrastructural characteristics of cell phenotype in alveolar wall vessels were observed by electron microscopy. Results mPAP increased by(18.41±0.37)mm Hg after 7-day of hypoxia,(P0.05). Pulmonary artery remodeling index and right ventricle hypertrophy became evident after 14-day of hypoxia. The myofibroblast phenotype was confirmed by electron microscopy, which revealed microfilaments and a well-developed rough endoplasmic reticulum in myofibroblast. TGF-β_1 mRNA expression in pulmonary arterial walls was increased by (0.385±0.028, P0.01) after 14 days of hypoxia,but showed no obvious changes after 3 or 7 days of hypoxia. In pulmonary tunica adventitia and tunica media, TGF-β_1 staining was poorly positive in control rats, but was markedly enhanced after 3 days of hypoxia(0.198±0.031,P0.01), reaching its peak after 7 days of hypoxia(0.267±0.035,P0.01). Expression of iNOS mRNA in control group was poorly positive in pulmonary arterial wall, the level of iNOS mRNA was markedly up -regulated after 3 days of hypoxia(0.245±0.036, P0.01), reaching its peak after 7 days of hypoxia (0.318±0.034, P0.01), then remained on the high level. Expression of iNOS protein in control group was poorly positive in pulmonary arterial tunica media, the level of iNOS protein was markedly up-regulated after 3 days (0.225±0.030, P0.01), reaching its peak after 7 days of hypoxia, then remained on the high level. Conclusions Induction of TGF-β_1 and iNOS expression after hypoxia and myofibroblasts formation may play a important role in hypoxic pulmonary vascular remodeling of rats.