The extracellular proteoglycanase ADAMTS-1 has critical roles in organogenesis and angiogenesis. We demonstrate here the functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan 4 in influencing adhesion, migration, and angiogenesis in vitro. Knockdown of ADAMTS-1 resulted in a parallel reduction in cell surface syndecan 4 that was not due to altered syndecan4 expression or internalisation, but was attributable to increased expression and activity of matrix metalloproteinase 9 (MMP-9), a known syndecan 4 sheddase. Knockdown of either syndecan 4 or ADAMTS-1 led to enhanced endothelial cell responses to exogenous vascular endothelial growth factor (VEGF), and increased microvessel sprouting in ex vivo aortic ring assays, correlating with reduced ability of the cells to sequester VEGF. On fibronectin, but not type 1 collagen matrices, knockdown of either ADAMTS-1 or syndecan 4 elicited increased migration and altered focal adhesion morphologies, with a higher proportion of larger focal adhesions and formation of long fibrillar integrin α5-containing focal adhesions. Integrin α5-null endothelial cells also displayed enhanced migration in response to ADAMTS-1/syndecan 4 knockdown, indicating that integrin α5 was not the mediator of the altered migratory behaviour. Plating of naïve endothelial cells on cellconditioned matrix from ADAMTS-1/syndecan 4 knockdown cells demonstrated that the altered behaviour was matrix dependent. Fibulin-1, a known ECM co-factor of ADAMTS-1, was expressed at reduced levels in ADAMTS-1/syndecan 4 knockdown cells. These findings support the notion that ADAMTS-1 and syndecan 4 are functionally interconnected in regulating cell migration and angiogenesis, via the involvement of MMP-9 and fibulin-1 as collaborators
