Perivascular cells regulate endothelial membrane type-1 matrix metalloproteinase activity.
Angiogenic stimuli selectively induced expression of membrane type-1 matrix metalloproteinase (MT1-MMP) transcripts and protein in human umbilical vein endothelial cells (HUVECs). Pro-MMP-2 activation was blocked by treatment with tissue inhibitor of metalloproteinases-2 (TIMP-2), but not by TIMP-1 or inhibitors of other proteinase classes. Anti-MT1-MMP antibodies abrogated recombinant pro-MMP-2 activation by plasma membranes, indicating that MT1-MMP is the main mediator of pro-MMP-2 activation in HUVECs. Cocultures of HUVECs with smooth muscle cells (SMC) or pericytes (PC) resulted in the suppression of HUVEC pro-MMP-2 activation. Treatment of A10 SMC conditioned media with a neutralising anti-TIMP-2 antibody prevented the suppression of HUVEC pro-MMP-2 activation. Inhibition of HUVEC MT1-MMP function by PC and SM3 SMC correlated with elevated TIMP-3 expression. Thus, perivascular supporting cells regulate the functions of proangiogenic MMPs elaborated by endothelial cells via selective expression of TIMPs. This interplay may be important for maintenance of blood vessel architecture and neovascularisation.
Lafleur
M A
MA
School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, England.
Forsyth
P A
PA
Atkinson
S J
SJ
Murphy
G
G
Edwards
D R
DR
D001483:Base Sequence; D002478:Cells, Cultured; D018920:Coculture Techniques; D017931:DNA Primers / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D004792:Enzyme Precursors; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D013755:Tetradecanoylphorbol Acetate