Endothelial progenitor cell-dependent angiogenesis requires localization of the full-length form of uPAR in caveolae
Endothelial progenitor cell-dependent angiogenesis requires localization of the full-length form of uPAR in caveolae
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DOI：
10.1182/blood-2011-02-338681
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发表时间：
2011-09-29
期刊：
影响因子：
20.3
通讯作者：
Fibbi, Gabriella
中科院分区：
文献类型：
--
作者：
Margheri, Francesca;Chilla, Anastasia;Fibbi, Gabriella
内皮型尿激酶型纤溶酶原激活剂受体(UPAR)被认为在血管生成中提供了一种调节机制。在这里，我们研究了uPAR在内皮集落形成细胞(ECFCs)中的促血管生成作用，ECFCs是在人脐血中发现的一种细胞群体，它体现了与高增殖率匹配的内皮前体细胞的所有特性。通过使用小窝干扰剂和小窝蛋白-1沉默，我们已经证明ECFC的血管生成特性依赖于小窝的完整性和这种特殊的膜内陷中全长uPAR的存在。反义寡核苷酸抑制uPAR的表达促进了小窝的破坏，提示uPAR是小窝组织的诱导者。血管内皮生长因子(VEGF)以其未降解形式促进uPAR在ECFC小窝中的积聚。我们还证明，依赖于血管内皮生长因子的ERK的磷酸化需要小窝的完整性以及小窝uPAR的表达。血管内皮生长因子的活性依赖于抑制ECFC MMP12的产生，从而导致MMP12依赖的uPAR截断受损。此外，MMP12在ECFC中的过表达抑制了体外和体内的血管形成。我们的数据表明，被适当设计为过度表达MMP12的ECFC的瘤内归巢可能有机会控制肿瘤血管生成和恶性细胞扩散所需的uPAR依赖的活动。(血。2011；118(13)：3743-3755)
Endothelial urokinase-type plasminogen activator receptor (uPAR) is thought to provide a regulatory mechanism in angiogenesis. Here we studied the proangiogenic role of uPAR in endothelial colony-forming cells (ECFCs), a cell population identified in human umbilical blood that embodies all of the properties of an endothelial progenitor cell matched with a high proliferative rate. By using caveolae-disrupting agents and by caveolin-1 silencing, we have shown that the angiogenic properties of ECFCs depend on caveolae integrity and on the presence of full-length uPAR in such specialized membrane invaginations. Inhibition of uPAR expression by antisense oligonucleotides promoted caveolae disruption, suggesting that uPAR is an inducer of caveolae organization. Vascular endothelial growth factor (VEGF) promoted accumulation of uPAR in ECFC caveolae in its undegraded form. We also demonstrated that VEGF-dependent ERK phosphorylation required integrity of caveolae as well as caveolar uPAR expression. VEGF activity depends on inhibition of ECFC MMP12 production, which results in impairment of MMP12-dependent uPAR truncation. Further, MMP12 overexpression in ECFC inhibited vascularization in vitro and in vivo. Our data suggest that intratumor homing of ECFCs suitably engineered to overexpress MMP12 could have the chance to control uPAR-dependent activities required for tumor angiogenesis and malignant cells spreading. (Blood. 2011; 118(13):3743-3755)