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J. Biol. Chem., Vol. 281, Issue 13, 8724-8731, March 31, 2006

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Loss of PECAM-1 Function Impairs Alveolarization^*

Horace M. DeLisser¹, Brian P. Helmke¹², Gaoyuan Cao, Patricia M. Egan^¶, Darren Taichman, Melane Fehrenbach, Aisha Zaman^¶, Zheng Cui^¶, Gopi S. Mohan^¶, H. Scott Baldwin^||3, Peter F. Davies, and Rashmin C. Savani^¶4

From the Pulmonary, Allergy and Critical Care Division, Department of Medicine, Institute for Medicine and Engineering, the ^¶Division of Neonatology, Department of Pediatrics, and the ^||Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318

The final stage of lung development in humans and rodents occurs principally after birth and involves the partitioning of the large primary saccules into smaller air spaces by the inward protrusion of septae derived from the walls of the saccules. Several observations in animal models implicate angiogenesis as critical to this process of alveolarization, but all anti-angiogenic treatments examined to date have resulted in endothelial cell (EC) death. We therefore targeted the function of platelet endothelial cell adhesion molecule, (PECAM-1), an EC surface molecule that promotes EC migration and has been implicated in in vivo angiogenesis. Administration of an anti-PECAM-1 antibody that inhibits EC migration, but not proliferation or survival in vitro, disrupted normal alveolar septation in neonatal rat pups without reducing EC content. Three-dimensional reconstruction of lungs showed that pups treated with a blocking PECAM-1 antibody had remodeling of more proximal branches resulting in large tubular airways. Subsequent studies in PECAM-1-null mice confirmed that the absence of PECAM-1 impaired murine alveolarization, without affecting EC content, proliferation, or survival. Further, cell migration was reduced in lung endothelial cells isolated from these mice. These data suggest that the loss of PECAM-1 function compromises postnatal lung development and provide evidence that inhibition of EC function, in contrast to a loss of viable EC, inhibits alveolarization.

Received for publication, November 1, 2005 , and in revised form, December 22, 2005.

^* This work was supported by Department of Defense Grant PR043482 (to H. M. D.), National Institutes of Health Grant HL079090 (to H. M. D.), Grants HL62472, HL62868, and HL075930 (to R. C. S.), and Grant NRSA HL10058 (to B. P. H.), and the Philadelphia Veterans Medical Center (to H. M. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text, a supplemental figure, and four supplemental movies.

¹ Both authors contributed equally to this work.

² Present address: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908.

³ Present address: Vanderbilt University Medical Center, Department of Pediatric Cardiology, Vanderbilt University, Nashville, TN 37232.

⁴ To whom correspondence should be addressed: MBChB, Rm. 416F, Abramson Research Center, Children's Hospital of Philadelphia, 3516 Civic Center Blvd., Philadelphia, PA 19104-4318. Tel.: 215-590-5507; Fax: 215-590-4267; E-mail: rsavani{at}mail.med.upenn.edu.

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