Cyclosporin A differentially inhibits multiple steps in VEGF induced angiogenesis in human microvascular endothelial cells through altered intracellular signaling.
Cyclosporin A differentially inhibits multiple steps in VEGF induced angiogenesis in human microvascular endothelial cells through altered intracellular signaling.
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DOI：
10.1186/1478-811x-2-3
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发表时间：
2004-06-02
期刊：
影响因子：
--
通讯作者：
Binion DG
中科院分区：
文献类型：
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作者：
Rafiee P;Heidemann J;Ogawa H;Johnson NA;Fisher PJ;Li MS;Otterson MF;Johnson CP;Binion DG
免疫抑制剂环孢素A （cyclosporin A, CsA）是一种阻断T细胞活化的钙调磷酸酶抑制剂，为器官移植提供了药理学基础。CsA对非免疫细胞群产生额外影响，并可能对微血管内皮细胞产生不利影响，导致慢性排斥反应，这是实体器官移植（包括小肠同种异体移植患者）的长期临床并发症和重要死亡原因。新血管的生长或血管生成是器官和组织中一个重要的内稳态机制，并根据生理需要调节血管种群。我们假设CsA会抑制人肠道微血管的血管生成能力。采用人肠道微血管内皮细胞（HIMEC）原代培养，评估CsA对内皮生长因子VEGF对血管生成的四项体外指标的影响，包括内皮应激纤维组装、迁移、增殖和成管。我们描述了CsA对VEGF刺激后细胞内信号机制的影响。CsA影响HIMEC中评估的所有VEGF诱导的血管生成事件。CsA不同程度地抑制了介导血管生成过程不同步骤的信号通路。CsA阻断VEGF诱导的转录因子NFAT核易位，激活p44/42 MAPK，部分抑制JNK和p38 MAPK。CsA以剂量依赖性的方式影响信号级联反应，并完全阻断COX-2的表达，COX-2与HIMEC血管生成完全相关。这些数据表明，CsA抑制微血管内皮细胞进行血管生成的能力，损害血管稳态机制，并导致慢性排斥反应相关的血管病变。
The immunosuppressive agent cyclosporin A (CsA), a calcineurin inhibitor which blocks T cell activation has provided the pharmacologic foundation for organ transplantation. CsA exerts additional effects on non-immune cell populations and may adversely effect microvascular endothelial cells, contributing to chronic rejection, a long-term clinical complication and significant cause of mortality in solid-organ transplants, including patients with small bowel allografts. Growth of new blood vessels, or angiogenesis, is a critical homeostatic mechanism in organs and tissues, and regulates vascular populations in response to physiologic requirements. We hypothesized that CsA would inhibit the angiogenic capacity of human gut microvessels. Primary cultures of human intestinal microvascular endothelial cells (HIMEC) were used to evaluate CsA's effect on four in vitro measures of angiogenesis, including endothelial stress fiber assembly, migration, proliferation and tube formation, in response to the endothelial growth factor VEGF. We characterized the effect of CsA on intracellular signaling mechanisms following VEGF stimulation. CsA affected all VEGF induced angiogenic events assessed in HIMEC. CsA differentially inhibited signaling pathways which mediated distinct steps of the angiogenic process. CsA blocked VEGF induced nuclear translocation of the transcription factor NFAT, activation of p44/42 MAPK, and partially inhibited JNK and p38 MAPK. CsA differentially affected signaling cascades in a dose dependent fashion and completely blocked expression of COX-2, which was integrally linked to HIMEC angiogenesis. These data suggest that CsA inhibits the ability of microvascular endothelial cells to undergo angiogenesis, impairing vascular homeostatic mechanisms and contributing to the vasculopathy associated with chronic rejection.