Changes in expression of vascular endothelial growth factor and its receptors in neonatal hypoxia-induced pulmonary hypertension
Changes in expression of vascular endothelial growth factor and its receptors in neonatal hypoxia-induced pulmonary hypertension
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DOI：
10.1203/01.pdr.0000169969.18669.d2
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发表时间：
2005-08-01
影响因子：
3.6
通讯作者：
Perreault, T
中科院分区：
文献类型：
--
作者：
Nadeau, S;Baribeau, J;Perreault, T
血管内皮生长因子（VEGF）是一种具有血管生成和血管活性的强效有丝分裂原。VEGF可以与两种类型的受体结合。VEGF受体2（VEGFR 2）主要负责通过一氧化氮（NO）释放对VEGF的扩张反应，而VEGFR 1可螯合配体。我们假设在新生儿缺氧诱导的肺动脉高压中，VEGF血管舒张减少。在暴露于常氧或缺氧（吸入氧分数0.10）14 d的1 d龄仔猪的离体灌注肺中评估扩张剂对VEGF的反应。采用定量夹心酶免疫分析法测定常氧或缺氧1、3、7、14 d仔猪血浆和肺动脉VEGF浓度。采用Western blot法检测各组大鼠肺动脉VEGF 1、VEGF 2和内皮型NO合成酶的表达。VEGF（10（-12）-10（-9）M）在14天常氧仔猪中诱导剂量依赖性舒张，而缺氧14天后血管舒张被消除。VEGF组织浓度通过缺氧而增加。与常氧相比，VEGFR 1表达在缺氧1、3和7 d后显著增加，之后恢复正常。缺氧14 d时VEGFR 2表达降低。然而，与常氧相比，内皮NO合酶的表达不受缺氧的影响。在新生儿缺氧诱导的肺动脉高压中，VEGF增加，而VEGF的血管舒张被取消。这种血管舒张减少可能是由于VEGFR 2表达减少。我们推测VEGFR 1的隔离作用也可能在一定程度上限制VEGF的血管保护作用，从而导致新生儿缺氧诱导的肺动脉高压的病理生理变化。
Vascular endothelial growth factor (VEGF) is a potent mitogen with angiogenic and vasoactive properties. VEGF can bind to two types of receptors. VEGF receptor 2 (VEGFR2) is mainly responsible for the dilator response to VEGF through nitric oxide (NO) release, whereas VEGFR1 may sequestrate the ligand. We hypothesized that in neonatal hypoxia-induced pulmonary hypertension, VEGF vasodilation is reduced. The dilator response to VEGF was assessed in isolated perfused lung of 1-d-old piglets that were exposed to either normoxia or hypoxia (fraction of inspired oxygen 0.10) for 14 d. The plasma and pulmonary artery concentration of VEGF was measured by quantitative sandwich enzyme immunoassay in piglets that were exposed to either normoxia or hypoxia for 1, 3, 7, or 14 d. The expression of VEGFR1, VEGFR2, and endothelial NO synthase in pulmonary artery was measured in the same study groups using Western blot analysis. VEGF (10(-12)-10(-9) M) induces a dose-dependent relaxation in 14-d normoxic piglets, whereas vasodilation is abolished after 14 d of hypoxia. VEGF tissue concentration is increased by hypoxia. VEGFR1 expression is dramatically increased after 1, 3, and 7 d of hypoxia compared with normoxia and returns to normal afterward. VEGFR2 expression is reduced by hypoxia at 14 d. However, endothelial NO synthase expression is not affected by hypoxia compared with normoxia. In neonatal hypoxia-induced pulmonary hypertension, VEGF is increased, whereas vasodilation to VEGF is abolished. This reduced vasodilation may be due to decreased VEGFR2 expression. We speculate that sequestration by VEGFR1 may also limit, to some extent, the vascular protecting effect of VEGF, thus contributing to the pathophysiologic changes seen in neonatal hypoxia-induced pulmonary hypertension.