ADAMTS9 Is a Cell-Autonomously Acting, Anti-Angiogenic Metalloprotease Expressed by Microvascular Endothelial Cells

• Published in: The American journal of pathology Vol. 176; no. 3; pp. 1494 - 1504
• Main Authors: Koo, Bon-Hun, Coe, David M., Dixon, Laura J., Somerville, Robert P.T., Nelson, Courtney M., Wang, Lauren W., Young, Mary Elizabeth, Lindner, Daniel J., Apte, Suneel S.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.03.2010; ASIP; American Society for Investigative Pathology
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAMTS9 Protein; Aging - metabolism; Animals; Biocatalysis; Biological and medical sciences; Cell Movement; Corneal Neovascularization - enzymology; Corneal Neovascularization - pathology; Embryo, Mammalian - enzymology; Embryo, Mammalian - pathology; Endothelial Cells - enzymology; Endothelial Cells - pathology; Enzyme Activation; Gene Knockdown Techniques; Humans; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mice; Mice, Inbred C57BL; Microvessels - enzymology; Microvessels - pathology; Neoplasm Transplantation; Neoplasms - blood supply; Neoplasms - enzymology; Neoplasms - pathology; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - pathology; Organ Specificity; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphorylation; Receptors, Vascular Endothelial Growth Factor - metabolism; Regular; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; Thrombospondin 1 - metabolism; Thrombospondins - metabolism; Vascular Endothelial Growth Factor A - metabolism; Microcirculation; Anatomic pathology; Endothelial cell; Antiangiogenic agent
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.2353/ajpath.2010.090655

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. β-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 factor 165, ADAMTS9 neither cleaved thrombospondins 1 and 2, nor bound vascular endothelial growth factor 165. 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.