IP-10 induces dissociation of newly formed blood vessels
IP-10 induces dissociation of newly formed blood vessels
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DOI：
10.1242/jcs.048793
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发表时间：
2009-06-15
影响因子：
4
通讯作者：
Wells, Alan
中科院分区：
文献类型：
--
作者：
Bodnar, Richard J.;Yates, Cecelia C.;Wells, Alan
切断组织修复中旺盛的维管生长的信号仍不明确。我们证明CXC趋化因子受体3 （CXCR3）的激活可介导新形成血管的退化。我们提供的证据表明，CXCR3在体内和体外新形成的血管上表达。CXCR3在受伤后7-21天在血管中表达，在未受伤或愈合的皮肤中检测不到。CXCL10 （IP-10）是一种存在于伤口溶解阶段的CXCR3配体，在体外或体内治疗内皮索时，即使存在血管生成因子，也会引起解离。与此一致的是，与野生型小鼠相比，缺乏CXCR3的小鼠在伤口组织中表达了更多的血管。然后，我们假设来自CXCR3的信号不仅限制血管生成，而且损害血管完整性以诱导血管退化。我们发现CXCR3的激活触发了mu-calpain活性，导致β 3整合素的细胞质尾部在calpain切割位点c'754和c'747处发生切割。IP-10刺激也激活了caspase 3，阻断caspase 3可防止细胞死亡，但不能阻止脊髓分离。这是第一个直接证据，证明细胞外信号机制通过CXCR3导致新形成的血管解离，随后导致细胞死亡。
The signals that prune the exuberant vascular growth of tissue repair are still ill defined. We demonstrate that activation of CXC chemokine receptor 3 (CXCR3) mediates the regression of newly formed blood vessels. We present evidence that CXCR3 is expressed on newly formed vessels in vivo and in vitro. CXCR3 is expressed on vessels at days 7-21 post-wounding, and is undetectable in unwounded or healed skin. Treatment of endothelial cords with CXCL10 (IP-10), a CXCR3 ligand present during the resolving phase of wounds, either in vitro or in vivo caused dissociation even in the presence of angiogenic factors. Consistent with this, mice lacking CXCR3 express a greater number of vessels in wound tissue compared to wildtype mice. We then hypothesized that signaling from CXCR3 not only limits angiogenesis, but also compromises vessel integrity to induce regression. We found that activation of CXCR3 triggers mu-calpain activity, causing cleavage of the cytoplasmic tail of beta 3 integrins at the calpain cleavage sites c'754 and c'747. IP-10 stimulation also activated caspase 3, blockage of which prevented cell death but not cord dissociation. This is the first direct evidence for an extracellular signaling mechanism through CXCR3 that causes the dissociation of newly formed blood vessels followed by cell death.