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© The Rockefeller University Press, 0021-9525/1998//1255 $5.00
The Journal of Cell Biology, Volume 140, Number 5, , 1998 1255-1263

Article

Integrin {alpha}vβ3 Requirement for Sustained Mitogen-activated Protein Kinase Activity during Angiogenesis



Brian P. Eliceiri, Richard Klemke, Staffan Strömblad, and David A. Cheresh

Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037

Angiogenesis depends on growth factors and vascular cell adhesion events. Integrins and growth factors are capable of activating the ras/MAP kinase pathway in vitro, yet how these signals influence endothelial cells during angiogenesis is unknown. Upon initiation of angiogenesis with basic fibroblast growth factor (bFGF) on the chick chorioallantoic membrane (CAM), endothelial cell mitogen-activated protein (MAP) kinase (ERK) activity was detected as early as 5 min yet was sustained for at least 20 h. The initial wave of ERK activity (5–120 min) was refractory to integrin antagonists, whereas the sustained activity (4–20 h) depended on integrin {alpha}vβ3, but not β1 integrins. Inhibition of MAP kinase kinase (MEK) during this sustained {alpha}vβ3-dependent ERK signal blocked the formation of new blood vessels while not influencing preexisting blood vessels on the CAM. Inhibition of MEK also blocked growth factor induced migration but not adhesion of endothelial cells in vitro. Therefore, angiogenesis depends on sustained ERK activity regulated by the ligation state of both a growth factor receptor and integrin {alpha}vβ3.

Abbreviations used in this paper: bFGF, basic fibroblast growth factor; CAM, chorioallantoic membrane; ECM, extracellular matrix; ERK, endothelial cell MAP kinase; HUVEC, human umbilical vein endothelial cell(s); MAP, mitogen-activated protein; MEK, MAP kinase kinase; MBP, myelin basic protein.

B.P. Eliceiri (1F32 HL09435) and R. Klemke (1F32CA67442) were supported by NRSA postdoctoral fellowships, and D.A. Cheresh was supported by grants CA50286, CA45726, and HL54444 from the National Institutes of Health. This is manuscript 10715-IMM from The Scripps Research Institute.

Address all correpondence to D.A. Cheresh, Departments of Immunology and Vascular Biology, The Scripps Research Institute, (IMM-24), 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (619) 784-8281. Fax: (619) 784-8926. E-mail: cheresh{at}scripps.edu


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