Effects of HGF/c-Met-mediated endothelial progenitor cells on pulmonary artery pressure and pulmonary vascular remodeling in rats with hypoxic pulmonary hypertension: A preliminary experimental study

Abstract:

Objective：To investigate the effects of hepatocyte growth factor（HGF）/c-Met-mediated endothelial progenitor cells（EPCs） on pulmonary artery pressure（PAP） and pulmonary vascular remodeling in rats with hypoxic pulmonary hypertension（HPH）. Methods：A rat model of HPH was established. Primary EPCs were iso－lated from the bone marrow of rats，cultured，and identified. The recombinant adenovirus plasmid carrying the c-Met gene was constructed and transfected into EPCs. The rats were divided into c-Met-EPCs group，EPCs group，pulmonary hypertension group，and normal group，with 10 rats in each group. c-Met-EPCs and EPCs were infused into the tail vein of rats in the c-Met-EPCs group and EPCs group，respectively，while normal saline was in－fused into the tail vein of rats in the pulmonary hypertension group and normal group. After normal feeding for a week，the mean PAP（mPAP） and right ventricular hypertrophy index（RVHI） were determined. The ultrastructural pathology of the pulmonary artery was observed under a transmission electron microscope，and the pathological sections of lung tissues were prepared to observe the histopathological changes of pulmonary arterioles. ELISA was used to determine the serum level of endothelin-1（ET-1），and the Griess method was used to determine the serum level of nitric oxide（NO）. Results：The measured values of mPAP for the c-Met-EPCs group，EPCs group，pulmonary hypertension group，and normal group were （23.17±3.07） mmHg，（30.85±3.15） mmHg，（33.55±5.47） mmHg，and （20.30±1.99） mmHg，respectively；the measured values of RVHI for the four groups were （32.48±2.38）%，（37.54±4.42）%，（38.53±2.81）%，and （26.05±3.05）%，respectively；the serum level of ET-1 for the four groups were （69.45±6.32） ng/L，（95.76±7.31） ng/L，（99.14±8.39） ng/L，and （62.35±6.06） ng/L，respectively；the serum level of NO for the four groups were （99.63±11.40） μmol/L，（56.07±3.32） μmol/L，（48.83±6.56） μmol/L，and （125.50±12.26） μmol/L，respectively. The mPAP，RVHI，and serum ET-1 level in the EPCs group and pulmonary hypertension group were significantly higher than those in the normal group（P<0.05），and the above-mentioned indices were significantly lower in the c-Met-EPCs group than in the EPCs group and pulmonary hypertension group（P<0.05）. The serum NO level in the EPCs group and pul－monary hypertension group was significantly lower than that in the normal group（P<0.05），and the serum NO level in the c-Met-EPCs group was significantly higher than that in the EPCs group and pulmonary hypertension group（P<0.05）. Transmission electron mi－croscopy showed obvious swelling of mitochondria and endoplasmic reticulum in pulmonary artery smooth muscle cells and dis－continuous distribution of endothelial cells in the EPCs group and pulmonary hypertension group，while swelling of mitochondria and endoplasmic reticulum in pulmonary artery smooth muscle cells was not obvious in the c-Met-EPCs group. The pathological sections of lung tissues showed obvious pulmonary vascular remodeling in the EPCs group and pulmonary hypertension group；however，the remodeling was reduced in the c-Met-EPCs group. Conclusion：HGF/c-Met-mediated EPCs can decrease PAP and improve pul－monary vascular remodeling in rats with HPH，possibly by inhibiting ET-1 release and promoting NO production.