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J. Biol. Chem., Vol. 279, Issue 37, 38277-38286, September 10, 2004

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Real-time Analysis of Very Late Antigen-4 Affinity Modulation by Shear^*

Gordon J. Zwartz, Alexandre Chigaev, Denise C. Dwyer, Terry D. Foutz, Bruce S. Edwards, and Larry A. Sklar

From the Department of Pathology and Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico 87131

Shear promotes endothelial recruitment of leukocytes, cell activation, and transmigration. Mechanical stress on cells caused by shear can induce a rapid integrin conformational change and activation, followed by an increase in binding to the extracellular matrix. The molecular mechanism of increased avidity is unknown. We have shown previously that the affinity of the ₄₁ integrin, very late antigen-4 (VLA-4), measured with an LDV-containing small molecule, varies with cellular avidity, measured from cell disaggregation rates. In this study, we measured in real time affinity changes of VLA-4 in response to shear. The resulting affinity was comparable with the state mediated by receptor signaling and corresponded in time with intracellular Ca²⁺ responses. Ca²⁺ ionophores and N,N'-[1,2-ethanediyl-bis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]]-, bis[(acetyloxy)methyl]ester demonstrate that the affinity regulation of VLA-4 in the presence of shear was related to Ca²⁺ signaling. Pertussis toxin treatment implicates G_i in an unknown pathway that connects shear, Ca²⁺ elevation, VLA-4 affinity, and cell avidity.

Received for publication, March 16, 2004 , and in revised form, June 16, 2004.

^* This work was supported by National Institutes of Health Grants RR14175/EB02022 and HL56384 (to L. A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors contributed equally to this work.

To whom correspondence and reprint requests should be addressed: Dept. of Pathology and Cancer Research and Treatment Center, MSC 08-4630, 1 University of New Mexico, Albuquerque, NM 87131-0001. Tel.: 505-272-6892; Fax: 505-272-6995; E-mail: lsklar{at}salud.unm.edu.

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