Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression
Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression
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DOI：
10.1182/blood-2011-01-331694
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发表时间：
2011-09-08
期刊：
影响因子：
20.3
通讯作者：
Pietras, Kristian
中科院分区：
文献类型：
--
作者：
Franco, Marcela;Roswall, Pernilla;Pietras, Kristian
血管内皮细胞（ECs）在形成过程中通过周细胞的募集得到稳定，无论是在正常组织中，还是在包括肿瘤在内的病理情况下的血管生成过程中。在肿瘤血管系统中，除了支持血流功能外，周细胞还保护内皮细胞免受抗血管生成治疗的影响，因此与临床对血管靶向药物的耐药性有关。然而，周细胞和内皮细胞之间的串扰的分子性质在很大程度上是未知的。在此，我们通过分离来自肿瘤的血管片段，鉴定了内皮细胞中周细胞诱导的生存信号，这些肿瘤经过基因或药理学改造，使周细胞丰富或缺乏。在体内和体外实验中，周细胞诱导肿瘤内皮细胞产生抗凋亡蛋白Bcl-w，从而保护细胞免受细胞毒性损伤。内皮细胞中依赖周细胞的存活信号是内皮细胞中涉及VEGF-A表达的自分泌循环的结果。通过分子和功能研究，我们在整合素α (v)下游的ECs中描绘了一条信号转导通路，其中NF-kappa B的激活是周细胞保护性串扰的起始事件。我们对肿瘤内皮细胞中周细胞来源的促生存信号的阐明对抗血管生成药物的临床开发具有潜在的重要意义，并为合理的多靶点癌症治疗提供了新的治疗靶点。（《血液》，2011;118(10):2906-2917）
Endothelial cells (ECs) in blood vessels under formation are stabilized by the recruitment of pericytes, both in normal tissues and during angiogenesis in pathologic situations, including neoplasia. In the tumor vasculature, besides supporting the functionality of blood flow, pericytes protect ECs from antiangiogenic therapies, and have thus been implicated in clinical resistance to vascular targeting drugs. However, the molecular nature of the crosstalk between pericytes and ECs is largely unchartered. Herein, we identified pericyte-induced survival signals in ECs by isolation of vascular fragments derived from tumors that had been genetically or pharmacologically engineered to be either pericyte-rich or pericyte-poor. Pericytes induced the antiapoptotic protein Bcl-w in tumor ECs both in vivo and in vitro, thereby conveying protection from cytotoxic damage. The pericyte-dependent survival signaling in ECs was consequential to enforcement of an autocrine loop involving VEGF-A expression in ECs. Through molecular and functional studies, we delineated a signal transduction pathway in ECs downstream of integrin alpha(v) involving activation of NF-kappa B as the initiating event of the protective crosstalk from pericytes. Our elucidation of pericyte-derived pro-survival signaling in tumor ECs has potentially important implications for clinical development of antiangiogenic drugs, and suggests new therapeutic targets for rational multitargeting of cancer. (Blood. 2011; 118(10): 2906-2917)