Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins αvβ3 and α6β1 in human umbilical vein endothelial cells
Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins αvβ3 and α6β1 in human umbilical vein endothelial cells
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DOI：
10.1074/jbc.m209288200
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发表时间：
2002-11-29
影响因子：
4.8
通讯作者：
Lau, LF
中科院分区：
文献类型：
--
作者：
Leu, SJ;Lam, SCT;Lau, LF
CYR61 （CCN1）是CCN家族的细胞外基质相关蛋白，该家族还包括CTGF （CCN2）、NOV （CCN3）、WISP-1 （CCN4）、WISP-2 （CCN5）和WISP-3 （CCN6）。纯化的CYR61可诱导角膜植入物新生血管形成，而CYR61缺失的小鼠因血管缺陷导致胚胎死亡，从而证实CYR61是血管生成的重要调节因子。Cyr61的异常表达与乳腺癌、伤口愈合以及动脉粥样硬化和再狭窄等血管疾病有关。在培养中，CYR61通过整合素介导的途径促进细胞粘附、迁移和增殖。本研究表明CYR61还能促进人脐静脉内皮细胞的细胞存活和小管形成。此外，我们剖析了CYR61对整合素受体的要求，以及它的促血管生成活性。因此，在整合素未被激活的早期传代内皮细胞中，cyr61诱导的细胞粘附和小管形成通过与整合素α (6) β(1)的相互作用发生。相比之下，在整合素被佛波酯或血管内皮生长因子激活的内皮细胞中，cyr61促进的细胞粘附、迁移、存活、生长因子诱导的有丝分裂和内皮小管形成都是通过整合素α (v) β介导的(3)。这些发现表明CYR61是整合素α (v) β(3)的激活依赖性配体和整合素α (6) β(1)的激活非依赖性配体，这些整合素介导CYR61的促血管生成活性存在差异。这些发现有助于明确CYR61作为血管生成调节剂的机制，为CYR61缺失小鼠血管完整性丧失和血管细胞凋亡增加提供了分子解释，并强调了CYR61在血管系统发育和稳态中的重要性。
CYR61 (CCN1) is an extracellular matrix-associated protein of the CCN family, which also includes CTGF (CCN2), NOV (CCN3), WISP-1 (CCN4), WISP-2 (CCN5), and WISP-3 (CCN6). Purified CYR61 induces neovascularization in corneal implants, and Cyr61-null mice suffer embryonic death due to vascular defects, thus establishing that CYR61 is an important regulator of angiogenesis. Aberrant expression of Cyr61 is associated with breast cancer, wound healing, and vascular diseases such as atherosclerosis and restenosis. In culture, CYR61 functions through integrin-mediated pathways to promote cell adhesion, migration, and proliferation. Here we show that CYR61 can also promote cell survival and tubule formation in human umbilical vein endothelial cells. Furthermore, we have dissected the integrin receptor requirements of CYR61 with respect to its proangiogenic activities. Thus, CYR61-induced cell adhesion and tubule formation occur through interaction with integrin alpha(6)beta(1) in early passage endothelial cells in which integrins have not been activated. By contrast, in endothelial cells in which integrins are activated by phorbol ester or vascular endothelial growth factor, CYR61-promoted cell adhesion, migration, survival, growth factor-induced mitogenesis, and endothelial tubule formation are all mediated through integrin alpha(v)beta(3). These findings indicate that CYR61 is an activation-dependent ligand of integrin alpha(v)beta(3) and an activation-independent ligand of integrin alpha(6)beta(1) and that these integrins differentially mediate the pro-angiogenic activities of CYR61. These findings help to define the mechanisms by which CYR61 acts as an angiogenic regulator, provide a molecular interpretation for the loss of vascular integrity and increased apoptosis of vascular cells in Cyr61-null mice, and underscore the importance of CYR61 in the development and homeostasis of the vascular system.