Effect Of Vascular Endothelial Growth Factor Receptor Inhibitor SU5416 On Pulmonary Vascular Remodeling In Neonatal Rats With HPH

Objective: To observe the effect of vascular endothelial growth factor(VEGF)receptor inhibitor SU5416 on pulmonary vascular remodeling and right ventricular hypertrophy in neonatal rats with HPH,and to explore the role of VEGF in neonatal rats with HPH.Methods: Forty neonatal rats were randomly divided into control group,HPH group,HPH+SU5416 group,and SU5416 group,with 10 rats in each group.The neonatal rats in the HPH+SU5416 group were subcutaneously injected with SU5416 20mg/kg every week and then were kept in the hypoxic chamber together with the neonatal rats in the HPH group(oxygen concentration 10%±0.5).The neonatal rats in SU5416 group were injected with SU5416 20mg/kg subcutaneously every week and then kept in normoxic environment together with the neonatal rats in control group.After 14 days of intervention,the neonatal rats in each group were sacrificed after measuring mean pulmonary artery pressure(RVSP)by direct manometry,and the lung tissue and heart tissue samples were collected.The right ventricle was isolated,and the right ventricle and left ventricle plus interventricular septum mass were weighed,and right ventricular hypertrophy index(RVHI)was calculated.After HE staining,the morphology of pulmonary vessels was observed under a light microscope,and the indexes of pulmonary vascular remodeling(MA and MT)were calculated.The expression levels of α-smooth muscle actin(α-SMA)and vascular endothelial growth factor(VEGF)in pulmonary vessels were detected by immunohistochemistry.Results: 1)RVSP: Compared with the control group,the neonatal rats in the HPH group and the HPH+SU5416 group had a significant increase in RVSP(P<0.05),and the SU5416 group had no significant increase in RVSP(P>0.05).The HPH+SU5416 group had a significant increase in pulmonary artery pressure compared with the HPH group(P<0.05),indicating that SU5416 aggravated pulmonary artery pressure in neonatal rats with HPH;2)Pulmonary vascular remodeling indicators(MA,MT): Compared with the control group,the neonatal rats in the HPH and HPH+SU5416groups had significant increases in MA and MT(P<0.05),and the HPH+SU5416 group had significantly higher MA and MT than the HPH group(P<0.05),suggesting that SU5416 aggravated pulmonary vascular remodeling in the neonatal rats with HPH.There was no significant difference in MA and MT between the SU5416 group and the control group(P>0.05);3)RVHI: Compared with the control group,the neonatal rats in the HPH and HPH+SU5416 groups had a significant increase in RVHI(P < 0.05),and the HPH+SU5416 group had a significantly higher RVHI than the HPH group(P<0.05),suggesting that SU5416 aggravated right ventricular hypertrophy in neonatal rats with HPH.There was no significant difference between SU5416 group and HPH group(P>0.05);4)Expression of α-SMA: Compared with the control group,the HPH group and the HPH+SU5416 group had a significant increase in the expression of α-SMA in pulmonary vessels(P<0.05),and the HPH+SU5416 group had a significantly higher expression ofα-SMA than the HPH group(P<0.05),suggesting that SU5416 aggravated pulmonary vascular muscularization in neonatal rats with HPH.There was no significant difference between SU5416 group and control group(P>0.05);5)Expression of VEGF: Compared with the control group,the HPH group and the HPH+SU5416 group had a significant increase in the expression of VEGF in pulmonary vessels(P < 0.05),and the HPH+SU5416 group had a significant increase compared with the HPH group(P<0.05),while the SU5416 group had no significant change compared with the control group.The difference was not statistically significant(P > 0.05).Conclusions: VEGF receptor inhibitor SU5416 aggravates pulmonary vascular remodeling and right ventricular hypertrophy in neonatal rats with HPH,which further proves that VEGF may play a protective role in the early formation of HPH in neonatal rats and participate in the pathogenesis of pulmonary vascular remodeling.