Zhang Yan, Furumura Minao, Morita Eishin
Department of Dermatology, Faculty of Medicine, Shimane University, Shimane, Japan.
Growth Factors. 2008 Jun;26(3):125-31. doi: 10.1080/08977190802105909.
Vascular endothelial growth factor (VEGF) is a pleiotropic factor that regulates embryonal vasculogenesis, tumor angiogenesis and vascular permeability. Among eight differential isoforms, VEGF 121 mainly regulates vascular permeability, while VEGF 165 induces angiogenesis. Our previous studies have suggested that VEGF 121 and VEGF 165 are mainly detected in the lesions of psoriasis and atopic dermatitis, especially VEGF 121. VEGF 121 is the most predominant isoform, which plays a major role in the increased vascular permeability in the aforementioned skin lesions. Thus, the differential expression of VEGF isoforms may be critical in determining either an angiogenic or a hyper-permeable state. However, the distinct VEGF signaling pathways that induce angiogenesis and vascular hyper-permeability in endothelial cells have never been demonstrated. To clarify the differential effects elicited by VEGF 121 and VEGF 165, we compared the biological responses and the signaling pathways activated by VEGF 121 and VEGF 165 in human umbilical vein endothelial cells (HUVEC). VEGF 165 significantly increased the level of phosphorylation in the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, whereas VEGF 121 had little to no effect. In contrast, VEGF 121 induced rapid activation of the Src pathway, while VEGF 165 showed a less pronounced and delayed activation of the Src pathway. Furthermore, the VEGF-induced hyper-permeability and cell proliferation of HUVEC were inhibited by a Src inhibitor (PP2) and a MEK inhibitor (PD98059), respectively. These results indicate that distinct signaling pathways confer different vascular responses to VEGF 121 and VEGF 165.
血管内皮生长因子（VEGF）是一种多效性因子，可调节胚胎血管生成、肿瘤血管生成和血管通透性。在八种不同的异构体中，VEGF 121主要调节血管通透性，而VEGF 165诱导血管生成。我们之前的研究表明，VEGF 121和VEGF 165主要在银屑病和特应性皮炎的皮损中检测到，尤其是VEGF 121。VEGF 121是最主要的异构体，在上述皮肤病变中血管通透性增加方面起主要作用。因此，VEGF异构体的差异表达可能在决定血管生成或高通透性状态方面至关重要。然而，在内皮细胞中诱导血管生成和血管高通透性的不同VEGF信号通路从未得到证实。为了阐明VEGF 121和VEGF 165引发的不同效应，我们比较了VEGF 121和VEGF 165在人脐静脉内皮细胞（HUVEC）中激活的生物学反应和信号通路。VEGF 165显著增加了丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）通路中的磷酸化水平，而VEGF 121几乎没有影响。相反，VEGF 121诱导Src通路快速激活，而VEGF 165对Src通路的激活则不明显且延迟。此外，Src抑制剂（PP2）和MEK抑制剂（PD98059）分别抑制了VEGF诱导的HUVEC高通透性和细胞增殖。这些结果表明，不同的信号通路赋予VEGF 121和VEGF 165不同的血管反应。
