Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension
Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension
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DOI：
10.1165/ajrcmb.18.6.2980
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发表时间：
1998-06-01
影响因子：
6.4
通讯作者：
Kourembanas, S
中科院分区：
文献类型：
--
作者：
Christou, H;Yoshida, A;Kourembanas, S
血管内皮生长因子（VEGF）是一种主要靶向内皮细胞的强效有丝分裂和通透性因子。至少有两个酪氨酸激酶受体，Flk-1和Flt-1。介导其作用，主要由内皮细胞表达。体外缺氧可上调VEGF和VEGF受体的表达，VEGF在缺氧诱导的血管生成中的作用已在多种疾病实体中得到广泛研究。尽管VEGF及其受体在肺中大量表达，但其在低氧性肺动脉高压及其伴随的血管重构中的作用尚不完全清楚。我们在这项体内研究中报道，缺氧增加了I-at肺中VEGF和FIk-1的mRNA水平，缺氧反应的动力学在受体和配体之间有所不同：FIk-1 mRNA对缺氧表现出双相反应，在缺氧暴露9-15小时后观察到mRNA水平的显著但短暂的上升，在3周后达到最高水平。相比之下，VEGF mRNA水平在急性缺氧时没有明显升高，但在缺氧1-3周后逐渐升高。通过原位杂交，VEGF mRNA主要定位于肺泡上皮细胞，与对照组相比，缺氧动物肺中的信号增加。抗VEGF抗体免疫组化染色发现VEGF肽遍布肺实质，与常氧动物相比，低氧动物的循环VEGF浓度明显高于常氧动物。均匀模糊染料外渗法测定肺血管通透性，正常氧与正常氧无显著差异；低氧动物，尽管在低氧动物中观察到通透性增加的趋势。这些发现提示VEGF可能在肺缺氧反应中起作用。
Vascular endothelial growth factor (VEGF) is a potent mitogenic and permeability factor targeting pre dominantly endothelial cells. At least two tyrosine kinase receptors, Flk-1 and Flt-1. mediate its action and are mostly expressed by endothelial cells. VEGF and VEGF receptor expression are upregulated by hypoxia in vitro and the role of VEGF in hypoxia-induced angiogenesis has been extensively studied in a variety of disease entities. Although VEGF and its receptors are abundantly expressed in the lung, their role in hypoxic pulmonary hypertension and the accompanying vascular remodeling are incompletely understood. We report in this in vivo study that hypoxia increases mRNA levels for both VEGF and FIk-1 in the I-at lung, The kinetics of the hypoxic response differ between receptor and ligand: FIk-1 mRNA showed a biphasic response to hypoxia with a significant, but transient, rise in mRNA levels observed after 9-15 h of hypoxic exposure and the highest levels noted after 3 wk. In contrast, VEGF mRNA levels did not show a significant increase with acute hypoxia, but increased progressively after 1-3 wk of hypoxia. By in situ hybridization, VEGF mRNA was localized predominantly in alveolar epithelial cells with increased signal in the lungs of hypoxic animals compared with controls. Inmmunohistochemical staining with anti-VEGF antibodies localized VEGF peptide throughout the lung parenchyma and was increased in hypoxic compared with normoxic animals, Furthermore, hypoxic animals had significantly higher circulating VEGF concentrations compared with normoxic controls. Lung vascular permeability as measured by extravasation of Evens Blur dye was not significantly different between normoxic and;hypoxic animals, although a tendency for increased permeability was seen in the hypoxic animals. These findings suggest a possible role for VEGF in the pulmonary response to hypoxia.