Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival
Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival
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DOI：
10.1096/fj.00-0693fje
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发表时间：
2001-05-01
期刊：
影响因子：
4.8
通讯作者：
Ellis, LM
中科院分区：
文献类型：
--
作者：
Reinmuth, N;Liu, WB;Ellis, LM
肿瘤小血管由周细胞包围的内皮细胞（ECs）组成。周细胞被认为是一种EC存活因子，但其作用机制尚不清楚。一种可能的介质VEGF促进血管生成、内皮细胞增殖和内皮细胞通透性，并保护内皮细胞免于凋亡。我们假设PDGF（血小板衍生生长因子）BB，一种从肿瘤和内皮细胞释放的细胞因子，通过诱导VEGF介导周细胞功能，进而影响内皮细胞的存活。使用两种周细胞样细胞系，10T1/2细胞（小鼠周细胞系）和人血管平滑肌细胞（hVSMCs），我们发现PDGF‐BB增加了VEGF mRNA的转录。尽管PDGF‐BB激活了有丝分裂原激活的蛋白激酶和磷脂酰肌醇3激酶（PI3‐K）途径，但PI3‐K途径的激活是诱导VEGF的最重要途径。来自结肠癌细胞的条件培养基也通过PI3‐K途径诱导周细胞样细胞中的VEGF，该途径被SU6668阻断，SU6668是一种酪氨酸激酶抑制剂，可阻断PDGF、VEGF和碱性成纤维细胞生长因子的受体。PDGF - BB预处理的hVSMCs条件培养基可阻止ECs的凋亡，这种作用被VEGF中和抗体部分消除。这些研究表明，周细胞可能通过增加VEGF的细胞因子信号传导保护内皮细胞免于凋亡。
Small tumor vessels are composed of endothelial cells (ECs) surrounded by pericytes. Pericytes are believed to be an EC survival factor, but their mechanism of action is unknown. One possible mediator, VEGF, promotes angiogenesis, EC proliferation, and EC permeability, and it protects ECs from apoptosis. We hypothesized that PDGF (platelet‐derived growth factor)‐BB, a cytokine released from tumor and ECs, mediates pericyte function by inducing VEGF, which in turn may affect EC survival. Using two pericyte‐like cell lines, 10T1/2 cells (murine pericyte cell line) and human vascular smooth muscle cells (hVSMCs), we showed that PDGF‐BB increased VEGF mRNA transcription. Although PDGF‐BB activated both the mitogen‐activated protein kinase and phosphatidylinositol 3‐kinase (PI3‐K) pathways, activation of the PI3‐K pathway was the most important pathway for VEGF induction. Conditioned medium derived from colon cancer cells also induced VEGF in pericyte‐like cells via the PI3‐K pathway, which was blocked by SU6668, a tyrosine kinase inhibitor that blocks the receptors for PDGF, VEGF, and basic fibroblast growth factor. Conditioned medium from hVSMCs pretreated with PDGF‐BB prevented apoptosis of ECs, and this effect was partially abrogated by neutralizing antibodies to VEGF. These studies suggest that pericytes may protect ECs from apoptosis, in part, by cytokine signaling that increases VEGF.