Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis.
Many tumor types express matrix metalloproteinase-1 (MMP-1); its collagenase activity facilitates both tumor cell invasion and metastasis. MMP-1 expression is also associated with increased angiogenesis; however, the exact mechanism by which this occurs is not clear. MMP-1 proteolytically activates protease activated receptor-1 (PAR-1), a thrombin receptor that is highly expressed in endothelial cells. Thrombin is also present in the tumor microenvironment, and its activation of PAR-1 is pro-angiogenic. It is currently unknown whether MMP-1 activation of PAR-1 induces angiogenesis in a similar or different manner compared with thrombin. We sought to determine the mechanism by which MMP-1 promotes angiogenesis and to compare the effects of MMP-1 with those of thrombin. Our results demonstrate that via PAR-1, MMP-1 activates mitogen-activated protein kinase signaling cascades in microvessel endothelial cells. Although thrombin activation of PAR-1 also induces signaling through these pathways, the time-course of activation appears to vary. Gene expression analysis revealed a possible consequence of these signaling differences as MMP-1 and thrombin induce expression of different subsets of pro-angiogenic genes. Furthermore, the combination of thrombin and MMP-1 is more angiogenic than either protease alone. These data demonstrate that MMP-1 acts directly on endothelial cells as a pro-angiogenic signaling molecule and also suggest that the effects of MMP-1 may complement the activity of thrombin to better facilitate angiogenesis and promote tumor progression.
Blackburn
Jessica S
JS
Department of Biochemistry, Dartmouth Medical School, Lebanon, NH 03756, USA.
Brinckerhoff
Constance E
CE
D001672:Biocompatible Materials / Q000378:metabolism; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000235:genetics / Q000378:metabolism*
D001672:Biocompatible Materials; D004338:Drug Combinations; D007797:Laminin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D044463:Receptor, PAR-1; C059485:matrigel; D003094:Collagen; D013917:Thrombin; D020781:Matrix Metalloproteinase 1