Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins αvβ3 and α6β1 in human umbilical vein endothelial cells

Shr Jeng Leu, Stephen C.T. Lam, Lester F. Lau

Research output: Contribution to journalArticlepeer-review

218 Citations (Scopus)

Abstract

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 α6β1 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 αvβ3. These findings indicate that CYR61 is an activation-dependent ligand of integrin αvβ3 and an activation-independent ligand of integrin α6β1 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.

Original languageEnglish
Pages (from-to)46248-46255
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number48
DOIs
Publication statusPublished - 29 Nov 2002
Externally publishedYes

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