Suppression of human microvascular endothelial cell invasion and morphogenesis with synthetic matrixin inhibitors. Targeting angiogenesis with MMP inhibitors.
Matrix metalloproteinases (MMPs, matrixins) are a family of zinc proteinases that digest extracellular matrix and play a very important role in normal development and pathological conditions such as cardiovascular diseases and cancer metastasis. Type IV collagenases (gelatinase A/MMP-2 and gelatinase B/MMP-9) may be critical in the early steps of angiogenesis, the digestion of basement membrane and the migration of endothelial cells from the existing blood vessels. Human dermal microvascular endothelial cells were cultured on type I collagen, type IV collagen, and reconstituted basement membrane Matrigel and differentiation was examined in the presence of potent synthetic inhibitors of MMPs. The thiol inhibitor MAG-283 had IC50 values of 480 nM and 3 nM against human interstitial collagenase (MMP-1) and MMP-2, respectively, and KI value of 2.2 nM against MMP-9. The sulfodiimine inhibitor YLL-224 had IC50 values of 180 nM, 63 nM, and 44 nM against MMP-1, -2, and -9, respectively. These inhibitors at very low micromolar concentrations inhibited cell-mediated type I collagen degradation and partially blocked cell invasion through type IV collagen. These inhibitors also suppressed endothelial differentiation, i.e., formation of capillary-like tubes on Matrigel and on type I collagen. These results suggest that collagen-degrading MMPs play an important role during the initiation of angiogenesis.
Jia
M C
MC
Department of Chemistry, Florida State University, Tallahassee 32306-4390, USA.
Schwartz
M A
MA
Sang
Q A
QA
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D001672:Biocompatible Materials; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D007797:Laminin; D008222:Lymphokines / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D008934:Mitogens / Q000494:pharmacology; D009024:Morphogenesis; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011509:Proteoglycans; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000577:Amides; D001672:Biocompatible Materials; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007097:Imines; D007211:Indoles; D007797:Laminin; D008222:Lymphokines; C413045:MAG 283; D061965:Matrix Metalloproteinase Inhibitors; D008934:Mitogens; D011509:Proteoglycans; D013438:Sulfhydryl Compounds; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C413046:YLL 224; C059485:matrigel; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate