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Integrins vβ3 and vβ5 Reciprocally Regulate Pulmonary Endothelial Barrier Function through Differential Effects on the Actin Cytoskeleton

¹ Lung Biology Center, ² Division of Pulmonary and Critical Care Medicine, University of California at San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to George Su, M.D., 1550 4th Street, Room 545, San Francisco, CA 94158. E-mail: george.su{at}ucsf.edu

We have shown the integrin vβ5 to be a central regulator of lung vascular permeability and pulmonary endothelial barrier function—both considered pathologic hallmarks of acute lung injury (ALI). vβ5 co-localizes with the closely related integrin, vβ3, at focal adhesions in pulmonary endothelial cells, and both integrins recognize overlapping ligands. Despite these similarities, inhibition of vβ3 and vβ5 have strikingly different effects on agonist-induced pulmonary endothelial permeability: inhibition of vβ3 dramatically enhances increased permeability, whereas inhibition of vβ5 prevents increased permeability. These integrins also have dramatically different effects on reorganization of the actin cytoskeleton in these cells. Blockade of vβ5 inhibits agonist-induced formation of actin stress fibers, whereas blockade of vβ3 specifically inhibits increases in cortical actin organization induced by sphingosine-1 phosphate and constitutively active Rac1. These observations suggest that vβ3 and vβ5 differentially regulate the pulmonary endothelial permeability response to edemagenic agonists through distinct effects on the actin cytoskeleton. Optimal therapies targeting integrin vβ5 for the treatment and/or prevention of ALI may thus be critically dependent on the development of selective antagonists that do not target the closely related integrin vβ3.

FOOTNOTES

Funded by NHLBI HL083950 (D.S.) and 1K08HL083097-01A1 (G.S.).

Conflict of Interest Statement: G.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.A. is a co-owner (with D.S.) of a filed patent (pending) covering blockade of integrin vβ5 for the treatment of acute lung injury. J.K.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.S. and A.A. are co-owners of a filed patent (pending) covering blockade of integrin vβ5 for the treatment of acute lung injury. He has had a sponsored research agreement with Biogen Idec to cover work on anti-integrin antibodies and acute lung injury for $150,000/year (total costs) since January 2002. UCSF co-owns all intellectual property of UCSF faculty, including the pending patent described above. The institution also collects indirect costs on the sponsored research agreement with Biogen Idec, described above.

(Received in original form November 13, 2007; accepted in final form November 16, 2007)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Su, G. Articles by Sheppard, D. Search for Related Content PubMed Articles by Su, G. Articles by Sheppard, D.