血管内皮生长因子抑制剂SU5416对新生大鼠缺氧性肺动脉高压肺血管重塑的研究

Effects of vascular endothelial growth factor inhibitor SU5416 on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension

目的探讨血管内皮生长因子(vascular endothelial growth factor, VEGF)抑制剂SU5416对新生大鼠缺氧性肺动脉高压(hypoxic pulmonary hypertension, HPH)肺血管重塑的影响。方法选择32只日龄7~10 d新生大鼠, 随机分为常氧组、缺氧组、SU5416+缺氧组、SU5416+常氧组并给予相应处理, 各组实验终点均为干预处理后14 d。测定各组新生大鼠右心室收缩压(right ventricular systolic pressure, RVSP)后留取心肺组织标本, 测定右心室肥厚指数(right ventricular hypertrophy index, RVHI);肺组织HE染色后光镜下观察肺血管形态学变化;计算肺小动脉中层壁厚度百分比(MT%)和中层横截面积百分比(MA%);免疫组化法检测肺血管中VEGF和α-平滑肌肌动蛋白(α-smooth muscle actin, α-SMA)的表达水平。结果缺氧组和SU5416+缺氧组新生大鼠RVSP、RVHI、MT%、MA%均明显高于常氧组、SU5416+常氧组(P<0.05), 且SU5416+缺氧组较缺氧组明显升高(P<0.05), 而SU5416+常氧组与常氧组比较差异无统计学意义(P>0.05);SU5416+缺氧组、缺氧组肺血管中α-SMA与VEGF表达水平明显高于常氧组和SU5416+常氧组(P<0.05), 且SU5416+缺氧组较缺氧组显著升高, 差异有统计学意义(P<0.05)。结论 VEGF抑制剂SU5416有加重HPH新生大鼠肺动脉高压及促进肺血管重塑的作用。

Objective To study the effects of vascular endothelial growth factor(VEGF)inhibitor SU5416 on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension(HPH).Methods Thirty-two neonatal rats(age 7~10 d)were randomly assigned into normoxia group,hypoxia group,SU5416+hypoxia group and SU5416+normoxia group according to corresponding treatments.The endpoint was 14 d after treatments.Right ventricular systolic pressure(RVSP)was measured and cardiac and pulmonary tissue were sampled on the day.Right ventricular hypertrophy index(RVHI)was calculated.After HE staining,the morphological changes of pulmonary vessels were observed under light microscope.Media thickness(MT),external diameter(ED),cross-sectional area of tunica media(MA)and total cross-sectional area(TA)of pulmonary arterioles were measured.MT%(MT/ED)and MA%(MA/TA)were calculated as indicators of pulmonary vascular remodeling.The levels of VEGF andα-smooth muscle actin(α-SMA)in pulmonary vessels were examined using immunohistochemistry(IHC)method.Results RVSP,RVHI,MT%and MA%in hypoxia group and SU5416+hypoxia group were significantly higher than normoxia group and SU5416+normoxia group(P<0.05).These indicators in SU5416+hypoxia group were also higher than hypoxia group(P<0.05),and no significant differences existed between SU5416+normoxia group and normoxia group(P>0.05).The levels ofα-SMA and VEGF in pulmonary vessels in SU5416+hypoxia group and hypoxia group were significantly higher than normoxia group and SU5416+normoxia group(P<0.05),andα-SMA and VEGF in SU5416+hypoxia group higher than hypoxia group(P<0.05).Conclusions VEGF inhibitor SU5416 may exacerbate pulmonary hypertension and increase pulmonary vascular remodeling in neonatal HPH rats.