Activation of VEGFR-2 signaling in response to moderate dose of ultraviolet B promotes survival of normal human keratinocytes.
Activation of VEGFR-2 signaling in response to moderate dose of ultraviolet B promotes survival of normal human keratinocytes.
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DOI：
10.1016/j.biocel.2011.10.022
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Jian-wei Zhu;Xian‐jie Wu;D. Luo;Zhongfa Lu;S. Cai;M. Zheng
中科院分区：
文献类型：
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作者：
Jian-wei Zhu;Xian‐jie Wu;D. Luo;Zhongfa Lu;S. Cai;M. Zheng
越来越多的证据表明，通过VEGF受体（VEGF）的信号传导超出了血管形成。最近，还发现VEGF在角质形成细胞和表皮附属物中组成型表达。在这里，我们表明，VEGF受体（包括VEGFR-1，VEGFR-2，和NRP-1）的表达显着增强由中等剂量的紫外线B（UVB）在正常人角质形成细胞和表皮。UVB引起的VEGFRs的表达升高不依赖于其天然配体VEGF的自分泌刺激，但主要通过缺氧和氧化应激介导。中等剂量UVB也促进VEGFR-1和VEGFR-2的酪氨酸磷酸化，这种作用也是VEGF无关的。蛋白激酶C（PKC）的α和δ亚型都是UVB诱导的VEGFR-1磷酸化所必需的，而VEGFR-2磷酸化只需要δ亚型。Src家族激酶（SFKs）的特异性抑制剂PP 2可完全抑制VEGF受体或PKC亚型的磷酸化，表明SFKs位于PKC和VEGF受体的上游。中剂量UVB诱导的VEGF对角质形成细胞具有抗凋亡作用，而高剂量UVB诱导的VEGF则作为炎症因子发挥作用。值得注意的是，VEGFR-2而不是VEGFR-1的中和加剧了UVB诱导的细胞死亡和角质形成细胞的存活减少。此外，VEGFR-2中和可抑制UVB对ERK 1/2和Akt的激活，表明VEGFR-2信号传导通过ERK 1/2和PI 3-K/Akt途径参与促生存机制。综上所述，我们首次证明了在中等剂量的UVB照射下，VEGFR-2信号被激活并促进角质形成细胞的存活。
Mounting evidence indicates that signaling via VEGF receptors (VEGFRs) extends beyond blood vessel formation. Recently, VEGFRs are also found to be constitutively expressed in keratinocytes and epidermal appendages. Here, we show that the expression of VEGFRs (including VEGFR-1, VEGFR-2, and NRP-1) was significantly enhanced by moderate dose of ultraviolet B (UVB) in normal human keratinocytes and epidermis. The elevated expression of VEGFRs by UVB was independent of autocrine stimulation by their natural ligand, VEGF, but mainly mediated through hypoxia and oxidative stress. Moderate dose UVB also promoted tyrosine phosphorylation of VEGFR-1 and VEGFR-2, this effect was again VEGF independent. Both α and δ isoforms of protein kinase C (PKC) were required for UVB-induced phosphorylation of VEGFR-1, but only the δ isoform was required for VEGFR-2 phosphorylation. The phosphorylation of VEGFRs or isoforms of PKC was completely inhibited by PP2, a specific inhibitor for Src family kinases (SFKs), indicating that SFKs are upstream of PKC and VEGFRs. Moderate dose UVB-induced VEGF exerted an anti-apoptotic effect for keratinocytes, whereas high dose UVB-induced VEGF played as an inflammatory factor. Of note, neutralization of VEGFR-2 but not VEGFR-1 exacerbated UVB-induced cell death and reduced survival of keratinocytes. Furthermore, VEGFR-2 neutralization inhibited the activation of ERK1/2 and Akt by UVB, suggesting that VEGFR-2 signaling was involved in the pro-survival mechanism via ERK1/2 and PI3-K/Akt pathway. Taken together, we demonstrate for the first time that VEGFR-2 signaling is activated and promotes survival of keratinocytes under moderate dose of UVB irradiation.