Potential Role for ADAM15 in Pathological Neovascularization in Mice

Abstract

ADAM15 (named for a disintegrin and metalloprotease 15, metargidin) is a membrane-anchored glycoprotein that has been implicated in cell-cell or cell-matrix interactions and in the proteolysis of molecules on the cell surface or extracellular matrix. To characterize the potential roles of ADAM15 during development and in adult mice, we analyzed its expression pattern by mRNA in situ hybridization and generated mice carrying a targeted deletion of ADAM15 (adam15^−/− mice). A high level of expression of ADAM15 was found in vascular cells, the endocardium, hypertrophic cells in developing bone, and specific areas of the hippocampus and cerebellum. However, despite the pronounced expression of ADAM15 in these tissues, no major developmental defects or pathological phenotypes were evident in adam15^−/− mice. The elevated levels of ADAM15 in endothelial cells prompted an evaluation of its role in neovascularization. In a mouse model for retinopathy of prematurity, adam15^−/− mice had a major reduction in neovascularization compared to wild-type controls. Furthermore, the size of tumors resulting from implanted B16F0 mouse melanoma cells was significantly smaller in adam15^−/− mice than in wild-type controls. Since ADAM15 does not appear to be required for developmental angiogenesis or for adult homeostasis, it may represent a novel target for the design of inhibitors of pathological neovascularization.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grant RO1 GM58668 and Memorial Sloan-Kettering Cancer Center Support grant NCI-P30-CA-08748, by the Samuel and May Rudin Foundation, and by the DeWitt Wallace Fund.

We thank Vera Suarez, Willie H. Mark, Jia-Hui Dong, Joanne Ingenito, and Liz Lacy for assistance and advice in generating adam15^−/− mice; Byung Lee, Eleanor Spumberg, Thadeous Kacmarczyk, Kenya Parks, and Anthony Zayas for assistance in mouse breeding and genotyping; Howard Petrie for the analysis of B- and T-cell ratio in spleen and peripheral lymphocytes; Mayumi Abe and Yasufumi Sato (Tohoku University, Sendai, Japan) for sharing results of a gene expression analysis of VEGF-treated HUVECs; Taha Merghoub and Pier-Paolo Pandolfi for differential blood counts and hematological analysis; and the MSKCC Transgenic Mouse Facility, Molecular Cytology Core Facility, and Research Animal Resources Facility.