Chronic Hypobaric Hypoxia Induces High Expression of Nitric Oxide in Holstein Heifers in Tibet

This study aimed to evaluate the adaptation of Holstein dairy cattle to the atmospheric pressure of Tibet (Lhasa city, altitude = 3,658 m, atmospheric partial pressure of oxygen = 100 mmHg). To our knowledge, this was the first report of Holstein dairy cattle adaptation to the chronic hypobaric hypoxia in Tibet. Unlike original high land animals, Holstein heifers were transported from the plain to Lhasa, and found both healthily adapted and sick individuals after one year exposure. Comparisons were made between healthy and brisket disease Holstein heifers. Heifers (age = 16 ± 2 month) were transported to Lhasa, after one year, 10 heifers with brisket disease (BW = 480 ± 18 kg) and 10 healthy ones (BW = 557 ± 14 kg) were chosen to evaluate the physiological effects of chronic hypoxia onto Holstein heifers. Plasma samples were analyzed for endothelial nitric oxide synthases (eNOS), inducible NOS (iNOS), total NOS (TNOS) and NOx (circulating NO and itrite/nitrate). Immunohistochemistry performed to detect remodeling of small pulmonary arteries. RT-PCR and western blots were used to determine the expression of lung eNOS and endothelin-1 (EDN-1). Respiratory rates (p < 0.001), oxygen saturation (p < 0.001) and blood velocity (p < 0.001) were significantly higher in healthy heifers. However, heart rates were higher in heifers with brisket disease (p < 0.05). Peripheral arterial pressures was significantly higher in healthy heifers than that in heifers with brisket disease (systolic pressure p < 0.0001, diastolic pressure p < 0.01, mean arterial pressures p < 0.01). Plasma eNOS (p < 0.001), iNOS (p < 0.001), TNOS (p < 0.05) and NOx (p < 0.0001) levels were higher in healthy heifers than those of heifers with brisket disease. Moreover, eNOS mRNA (p < 0.01) and protein (p < 0.01) were higher expressed in healthy lungs. Immunostaining revealed that eNOS was highly expressed in the intima of pulmonary arterioles (p < 0.01). In addition, EDN-1 mRNA (p< 0.05) and protein (p< 0.01) levels were both reduced in healthy heifers compared with heifers with brisket disease. Heifers with brisket disease displayed small pulmonary arterial (diameter < 100 µm) adventitial thickening (p < 0.001), proliferation of smooth muscle cells (p < 0.001) and low eNOS expression in the intima (p < 0.01) than healthy heifers. In conclusion, it is possible that highly expressed NOS dilate reconstruction of vasculature, maintain blood pressure and attenuate vascular remodeling to protect against pulmonary hypertension progression.