Potential role for ADAM15 in pathological neovascularization in mice.
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.
Horiuchi
Keisuke
K
Cellular Biochemistry and Biophysics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Weskamp
Gisela
G
Lum
Lawrence
L
Hammes
Hans-Peter
HP
Cai
Hui
H
Brodie
Thomas A
TA
Ludwig
Thomas
T
Chiusaroli
Riccardo
R
Baron
Roland
R
Preissner
Klaus T
KT
Manova
Katia
K
Blobel
Carl P
CP
D051722:ADAM Proteins; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005434:Flow Cytometry; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D008666:Metalloendopeptidases / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009389:Neovascularization, Pathologic; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D012164:Retinal Diseases / Q000473:pathology; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins / Q000166:cytology
D018076:DNA, Complementary; D008565:Membrane Proteins; D012333:RNA, Messenger; D051722:ADAM Proteins; C098660:ADAM15 protein, human; C490902:Adam15 protein, mouse; D008666:Metalloendopeptidases