Vascular Dysfunctional-Related Gene Expressions In The Neonatal Hypoxia-induced Pulmonary Arterial Hypertension Rat Model

Objective1.To establish the neonatal hypoxia-induced pulmonary arterial hypertension rat model,monitor hemodynamic changes and assess growth parameters.2.To analyze the vascular dysfunctional-related gene expressions in the neonatal hypoxia-induced pulmonary arterial hypertension rat model.Methods1.The establishment of animal model: Neonatal Sprague-Dawley rats and their dams were randomly assigned to the control group and hypoxia group.The control pups were maintained with their dams under normoxic conditions(room air).The hypoxia pups were placed in a hypoxic chamber with 11%-12% oxygen for 14 days.2.Assessment of the model: After 14 days of hypoxic exposure,the right ventricular systolic pressure(RVSP)was measured as the indicator of pulmonary arterial pressure.Right ventricular hypertrophy was assessed by the Fulton index(right ventricular weight/weight of left ventricle plus interventricular septum)and histologicalanalysis.3.Measurement of growth parameters including body weight,lung weight and heart weight.The lung weight/body weight and heart weight/body weight were also calculated.4.Assessment of lung development: The Hematoxylin-eosin-stained lung tissue sections were used to analyze changes in morphology and radial alveolar counts(RAC).5.Evaluation of pulmonary microvessel density: The number of von-Willebrand Factor(vWF)-positive pulmonary microvessels was calculated.6.Real-time quantitative PCR was used to analyze the vascular dysfunctionalrelated gene expressions in the neonatal hypoxia-induced pulmonary arterial hypertension rat model.Results1.The hypoxia group showed a significant increase in the RVSP,Fulton index and the right ventricular wall thickness compared with those of the control group.2.The hypoxia group showed a reduction in the body weight coupled with an increase in the lung to body weight ratio and the heart to body weight ratio.3.The hypoxic neonatal rats exhibited abnormal pulmonary morphology,as evidenced by an increase in air space area and a decrease in radial alveolar count.4.The pulmonary microvessel density was increased in the hypoxic neonatal rats.5.The mRNA levels of ET-1(endothelin-1),VEGF(vascular endothelial growth factor),PDK1(pyruvate dehydrogenase kinase 1)and PKM2(pyruvate kinase muscle isozyme 2)were significantly upregulated in the hypoxia group compared with those in the control group.Conclusions1.Continuous postnatal hypoxic exposure impaired alveolar formation accompanied by augmented angiogenesis.2.Continuous postnatal hypoxic exposure resulted in changes in the m RNA levels of genes associated with vascular dysfunction,which might be the contributing factors in the pathogenesis of pulmonary arterial hypertension.