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Molecular and Cellular Biology, May 2009, p. 2694-2703, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01460-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

ADAM9 Is Involved in Pathological Retinal Neovascularization{triangledown}

Victor Guaiquil,1,{dagger} Steven Swendeman,1,{dagger} Tsunehiko Yoshida,2 Sai Chavala,3 Peter A. Campochiaro,2 and Carl P. Blobel1,4*

Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021,1 Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287,2 Department of Ophthalmology, Duke University Medical Center, P.O. Box 3802, Durham, North Carolina 27710,3 Departments of Medicine and Physiology, Biophysics, and Systems Biology, Weill Medical College of Cornell University, New York, New York 100214

Received 17 September 2008/ Returned for modification 20 October 2008/ Accepted 26 February 2009

Pathological ocular neovascularization, caused by diabetic retinopathy, age-related macular degeneration, or retinopathy of prematurity, is a leading cause of blindness, yet much remains to be learned about its underlying causes. Here we used oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) to assess the contribution of the metalloprotease-disintegrin ADAM9 to ocular neovascularization in mice. Pathological neovascularization in both the OIR and CNV models was significantly reduced in Adam9–/– mice compared to wild-type controls. In addition, the level of ADAM9 expression was strongly increased in endothelial cells in pathological vascular tufts in the OIR model. Moreover, tumor growth from heterotopically injected B16F0 melanoma cells was reduced in Adam9–/– mice compared to controls. In cell-based assays, the overexpression of ADAM9 enhanced the ectodomain shedding of EphB4, Tie-2, Flk-1, CD40, VCAM, and VE-cadherin, so the enhanced expression of ADAM9 could potentially affect pathological neovascularization by increasing the shedding of these and other membrane proteins from endothelial cells. Finally, we provide the first evidence for the upregulation of ADAM9-dependent shedding by reactive oxygen species, which in turn are known to play a critical role in OIR. Collectively, these results suggest that ADAM9 could be an attractive target for the prevention of proliferative retinopathies, CNV, and cancer.

* Corresponding author. Mailing address: Arthritis and Tissue Degeneration Program, Caspary Research Building, Rm. 426, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. Phone: (212) 606-1429. Fax: (212) 774-2560. E-mail: blobelc{at}hss.edu

{triangledown} Published ahead of print on 9 March 2009.

{dagger} V.G. and S.S. contributed equally.

Molecular and Cellular Biology, May 2009, p. 2694-2703, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01460-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Franzke, C.-W., Bruckner-Tuderman, L., Blobel, C. P. (2009). Shedding of Collagen XVII/BP180 in Skin Depends on Both ADAM10 and ADAM9. J. Biol. Chem. 284: 23386-23396 [Abstract] [Full Text]  


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