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From the Vascular Medicine and Atherosclerosis Unit,*
Cardiovascular Division, Department of Medicine, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts, and Geneva
Biomedical Research Institute,
Geneva, Switzerland
Neovascularization frequently accompanies chronic immune responses
characterized by T cell infiltration and activation. Angiogenesis
requires endothelial cells (ECs) to penetrate extracellular
matrix, a process that involves matrix metalloproteinases
(MMPs). We report here that activated human T cells mediate
contact-dependent expression of MMPs in ECs through CD40/CD40 ligand
signaling. Ligation of CD40 on ECs induced de novo
expression of gelatinase B (MMP-9), increased interstitial
collagenase (MMP-1) and stromelysin (MMP-3), and activated
gelatinase A (MMP-2). Recombinant human CD40L induced expression of
MMPs by human vascular ECs to a greater extent than did maximally
effective concentrations of interleukin-1ß or tumor necrosis
factor-
. Moreover, activation of human vascular ECs through
CD40 induced tube formation in a three-dimensional fibrin matrix gel
assay, an effect antagonized by a MMP inhibitor. These results
demonstrated that activation of ECs by interaction with T cells induced
synthesis and release of MMPs and promoted an angiogenic function of
ECs via CD40L-CD40 signaling. As vascular cells at the sites of chronic
inflammation, such as atherosclerotic plaques, express
CD40 and its ligand, our findings suggest that ligation of CD40
on ECs can mediate aspects of vascular remodeling and neovessel
formation during atherogenesis and other chronic immune
reactions.
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F. Tronc, Z. Mallat, S. Lehoux, M. Wassef, B. Esposito, and A. Tedgui Role of Matrix Metalloproteinases in Blood Flow-Induced Arterial Enlargement : Interaction With NO Arterioscler. Thromb. Vasc. Biol., December 1, 2000; 20 (12): e120 - e126. [Abstract] [Full Text] [PDF]
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M. Melter, M. E. J. Reinders, M. Sho, S. Pal, C. Geehan, M. D. Denton, D. Mukhopadhyay, and D. M. Briscoe Ligation of CD40 induces the expression of vascular endothelial growth factor by endothelial cells and monocytes and promotes angiogenesis in vivo Blood, December 1, 2000; 96(12): 3801 - 3808. [Abstract] [Full Text] [PDF]
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 U. Schonbeck, G. K. Sukhova, K. Shimizu, F. Mach, and P. Libby Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice PNAS, June 20, 2000; 97(13): 7458 - 7463. [Abstract] [Full Text] [PDF]
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 A. W. Griffioen and G. Molema Angiogenesis: Potentials for Pharmacologic Intervention in the Treatment of Cancer, Cardiovascular Diseases, and Chronic Inflammation Pharmacol. Rev., June 1, 2000; 52(2): 237 - 268. [Abstract] [Full Text] [PDF]
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U. Schonbeck, F. Mach, G. K. Sukhova, M. Herman, P. Graber, M. R. Kehry, and P. Libby CD40 Ligation Induces Tissue Factor Expression in Human Vascular Smooth Muscle Cells Am. J. Pathol., January 1, 2000; 156(1): 7 - 14. [Abstract] [Full Text] [PDF]
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L. Biancone, V. Cantaluppi, M. Boccellino, L. Del Sorbo, S. Russo, A. Albini, I. Stamenkovic, and G. Camussi Activation of CD40 Favors the Growth and Vascularization of Kaposi's Sarcoma J. Immunol., December 1, 1999; 163(11): 6201 - 6208. [Abstract] [Full Text] [PDF]
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C. Phan, A. W. McMahon, R. C. Nelson, J. F. Elliott, and A. G. Murray Activated Lymphocytes Promote Endothelial Cell Detachment from Matrix: A Role for Modulation of Endothelial Cell {beta}1 Integrin Affinity J. Immunol., October 15, 1999; 163(8): 4557 - 4563. [Abstract] [Full Text] [PDF]
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