Abstract
ABSTRACTADAMTS-1 is an extracellular protease with critical roles in organogenesis and angiogenesis. Here we demonstrate a functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan-4 in influencing adhesion, migration and angiogenesis. Knockdown of ADAMTS-1 in endothelial cells resulted in a parallel reduction in cell surface syndecan-4, attributable to increased matrix metalloproteinase-9 (MMP9) activity. Knockdown of either ADAMTS-1 or syndecan-4 increased cellular responses to vascular endothelial growth factor A isoform VEGFA164, and increased ex vivo aortic ring microvessel sprouting. On fibronectin, knockdown of either protein enhanced migration and promoted formation of long α5 integrin-containing fibrillar adhesions. However, integrin α5 null cells still showed increased migration in response to ADAMTS-1 and syndecan-4 siRNA treatment. Plating of naïve endothelial cells on cell-conditioned matrix from ADAMTS-1 and syndecan-4 knockdown cells demonstrated that the altered adhesive behaviour was matrix dependent, and this correlated with a lack of expression of fibulin-1: an extracellular matrix co-factor for ADAMTS-1 that is known to inhibit migration. These findings support the notion that ADAMTS-1 and syndecan-4 are functionally interconnected in regulating cell migration and angiogenesis, via collaboration with MMP9 and fibulin-1.This article has an associated First Person interview with the first author of the paper.
Highlights
The ADAMTS family of extracellular proteases includes 19 members in humans, with diverse roles in tissue development and homeostasis (Kuno et al, 1997; Porter et al, 2005)
Our initial hypothesis was that as ADAMTS-1 has been reported to cleave the N-terminal domain of syndecan-4, depletion of ADAMTS-1 would result in accumulation of syndecan-4 on the cell surface (RodríguezManzaneque et al, 2009)
Flow cytometric analysis revealed that small interfering RNA (siRNA) knockdown of ADAMTS-1 resulted in a significant concomitant decrease in cell surface syndecan-4, equivalent to that seen with syndecan-4 knockdown (Fig. 1A)
Summary
The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of extracellular proteases includes 19 members in humans, with diverse roles in tissue development and homeostasis (Kuno et al, 1997; Porter et al, 2005). Their essential functions are underlined by the recognition that several family members are encoded by genes that are responsible for inherited genetic disorders when mutated, while others are. The surviving female mice suffer from infertility, due to the ineffective cleavage of versican during ovarian maturation (Krampert et al, 2005; Mittaz et al, 2004; Shindo et al, 2000)
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