ADAMTS proteases in vascular biology

Abstract

ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteases comprise the most recently discovered branch of the extracellular metalloenzymes. Research during the last 15years, uncovered their association with a variety of physiological and pathological processes including blood coagulation, tissue repair, fertility, arthritis and cancer. Importantly, a frequent feature of ADAMTS enzymes relates to their effects on vascular-related phenomena, including angiogenesis. Their specific roles in vascular biology have been clarified by information on their expression profiles and substrate specificity. Through their catalytic activity, ADAMTS proteases modify rather than degrade extracellular proteins. They predominantly target proteoglycans and glycoproteins abundant in the basement membrane, therefore their broad contributions to the vasculature should not come as a surprise. Furthermore, in addition to their proteolytic functions, non-enzymatic roles for ADAMTS have also been identified expanding our understanding on the multiple activities of these enzymes in vascular-related processes.

Keywords: ADAMTS; angiogenesis; extracellular proteolysis; vasculature.

Fig. 1.

Schematic diagram of ADAMTS proteases and anti-angiogenic effects. A. The structure of ADAMTS proteases includes a protease domain and an ancillary region. The protease domain contains a pro-domain, a catalytic motif and a disintegrin-like module. The ancillary region includes at least one TSR, a cysteine-rich domain, and a spacer fragment, that may or may not be followed by a variable number of additional TSR domains and other motifs. B. The anti-angiogenic effects of ADAMTS are classified in non-enzymatic (right) and enzymatic (left). Non-enzymatic effects are mediated mainly by the TSRs but additional motifs might also contribute. The enzymatic effects are naturally linked to the relevance of the substrate to vascular function. ADAMTS proteases whose catalytic activities provoke anti-angiogenic effects include: proteoglycanases, mucin-proteoglycanases and vWF-protease. Abbreviations: Cys — cysteine-rich domain; Disin — disintegrin-like module; TSR — thrombospondin type I repeat.

Fig. 2.

Substrates of ADAMTS proteases, distribution in relation to blood vessels and functions. ADAMTS proteases can be catalytically active either as full-length proteins or as truncated versions of enzymatically active fragments, after the release of their C-terminal regions. Most of ADAMTS substrates are components of the extracellular matrix, associated to specific cell types, or present in the vascular basement membrane (as indicated in panel). The modification of these substrates by proteolysis affects the activities of endothelial cells and pericytes. Abbreviations: BM — basement membrane; EC — endothelial cell; ECM — extracellular matrix.