ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells.
The metalloprotease ADAMTS9 participates in melanoblast development and is a tumor suppressor in esophageal and nasopharyngeal cancer. ADAMTS9 null mice die before gastrulation, but, ADAMTS9+/- mice were initially thought to be normal. However, when congenic with the C57Bl/6 strain, 80% of ADAMTS9+/- mice developed spontaneous corneal neovascularization. beta-Galactosidase staining enabled by a lacZ cassette targeted to the ADAMTS9 locus showed that capillary endothelial cells (ECs) in embryonic and adult tissues and in capillaries growing into heterotopic tumors expressed ADAMTS9. Heterotopic B.16-F10 melanomas elicited greater vascular induction in ADAMTS9+/- mice than in wild-type littermates, suggesting a potential inhibitory role in tumor angiogenesis. Treatment of cultured human microvascular ECs with ADAMTS9 small-interfering RNA resulted in enhanced filopodial extension, decreased cell adhesion, increased cell migration, and enhanced formation of tube-like structures on Matrigel. Conversely, overexpression of catalytically active, but not inactive, ADAMTS9 in ECs led to fewer tube-like structures, demonstrating that the proteolytic activity of ADAMTS9 was essential. However, unlike the related metalloprotease ADAMTS1, which exerts anti-angiogenic effects by cleavage of thrombospondins and sequestration of vascular endothelial growth factor165, ADAMTS9 neither cleaved thrombospondins 1 and 2, nor bound vascular endothelial growth factor165. Taken together, these data identify ADAMTS9 as a novel, constitutive, endogenous angiogenesis inhibitor that operates cell-autonomously in ECs via molecular mechanisms that are distinct from those used by ADAMTS1.
Koo
Bon-Hun
BH
Department of Biomedical Engineering (ND20), Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Coe
David M
DM
Dixon
Laura J
LJ
Somerville
Robert P T
RP
Nelson
Courtney M
CM
Wang
Lauren W
LW
Young
Mary Elizabeth
ME
Lindner
Daniel J
DJ
Apte
Suneel S
SS
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071119:ADAMTS9 Protein; D000375:Aging / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis; D002465:Cell Movement; D016510:Corneal Neovascularization / Q000201:enzymology / Q000473:pathology; D004622:Embryo, Mammalian / Q000201:enzymology / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000201:enzymology* / Q000473:pathology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D009928:Organ Specificity; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D019699:Thrombospondins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099262:Thrombospondin 2
D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D040262:Receptors, Vascular Endothelial Growth Factor; D019700:Thrombospondin 1; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D000099262:Thrombospondin 2; C412869:ADAMTS9 protein, human; C545434:Adamts9 protein, mouse