Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD:: morphological impact of VEGFR-2 inhibition
Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD:: morphological impact of VEGFR-2 inhibition
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DOI：
10.1152/ajplung.00116.2005
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发表时间：
2006-05-01
影响因子：
4.9
通讯作者：
Kirkham, PA
中科院分区：
文献类型：
--
作者：
Marwick, JA;Stevenson, CS;Kirkham, PA
VEGF是血管系统发育和维持的基础。通过VEGF受体（VEGFR）-2/激酶插入结构域受体（KDR）的VEGF（165）信号传导是一个高度调节的过程，涉及与磷脂酰肌醇蛋白聚糖（GYP）-1和神经纤毛蛋白（NRP）-1形成三级复合物。VEGF和VEGFR-2表达在肺气肿肺中均降低;然而，在体内以及在患有和不患有慢性阻塞性肺疾病（COPD）的吸烟者中，通过VEGFR-2复合物响应于香烟烟雾暴露来调节VEGF 165信号传导的机制仍然未知。我们假设香烟烟雾暴露破坏了VEGF（165）-VEGFR-2复合物，这是肺气肿发病机制中的一种潜在机制。我们发现，香烟烟雾暴露降低NRP-1和GYP-1以及VEGF和VEGFR-2在大鼠肺中的水平，并且与非吸烟者相比，吸烟者和COPD患者肺中的VEGF、VEGFR-2、GYP-1和NRP-1表达也降低。此外，我们的数据表明，单独用NVP-AAD 777特异性抑制VEGFR-2似乎不会导致成年大鼠肺气肿。由于VEGF（165）和VEGFR-2表达在肺气肿肺中均降低，GYP-1和NRP-1表达降低可能进一步破坏VEGF（165）-VEGFR-2信号传导。这本身是否是诱导内皮细胞凋亡和肺气肿患者肺血管化减少的关键，目前尚不清楚。然而，恢复VEGF（165）-VEGFR-2复合物的靶向治疗可促进内皮细胞存活并有助于改善肺气肿。
VEGF is fundamental in the development and maintenance of the vasculature. VEGF(165) signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF165 signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease ( COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF(165)-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF(165) and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF(165)-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF(165)-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.