Activity of MMP-19 inhibits capillary-like formation due to processing of nidogen-1

• DOI: 10.1007/s00018-004-4105-0
• Publication Date: 2004-07-05T11:33:47Z
• Authors: B. Titz; S. Dietrich; T. Sadowski; C. Beck; A. Petersen; R. Sedlacek
• Keywords: 0303 health sciences; 03 medical and health sciences; Membrane Glycoproteins; Neovascularization, Pathologic; Matrix Metalloproteinases, Secreted; Tumor Cells, Cultured; Humans; Metalloendopeptidases; Endothelium; Cell Division; Protein Structure, Tertiary

Matrix metalloproteinase 19 (MMP-19) is able to process various proteins of the basement membrane. To investigate the impact of MMP-19 activity on endothelial cells in the context of tumor extracellular matrix (ECM), we treated Matrigel matrix with an active recombinant MMP-19 and analyzed its effect on capillary-like formation. Human microvascular endothelial cells (HMEC-1) could not form capillary-like formation on Matrigel treated with recombinant MMP-19. Analyzing the Matrigel proteins, we found that MMP-19 preferentially cleaved nidogen-1. The cleavage site of nidogen-1 was mapped to Thr867-Leu868. This cleavage separates the G3 globular domain containing the binding site for the gamma1 chain of laminin-1 and collagen IV and thus abolishes the capacity of nidogen-1 to cross-link ECM proteins. Anti-nidogen antibodies directed against the G3 domain of nidogen-1 inhibited the capillary-like structure formation to a similar extent as MMP-19. Since nidogen-1 is thought to stabilize microvessels, MMP-19 might be one of the enzymes that interferes with stabilization or maturation of nascent vasculature.