T Lymphocytes Induce Endothelial Cell Matrix Metalloproteinase Expression by a CD40L-Dependent Mechanism

Abstract

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-1beta or tumor necrosis factor-alpha. 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.

Inhibitory Effects of Glycoprotein IIb/IIIa Antagonists and Aspirin on the Release of Soluble CD40 Ligand During Platelet Stimulation

“…28 CD40-CD40L interaction is also involved in plaque stability, most likely because of the CD40L-induced release of matrix metalloproteinases. 29,30 Elevated levels of sCD40L are found in patients experiencing vascular inflammation (for example, in acute coronary syndromes, 14,19 peripheral arterial occlusive disease, 31 and cardiopulmonary and bypass surgery 16 ). Population studies have established that elevated plasma levels of sCD40L are a risk factor for future cardiovascular events.…”

Engagement of Glycoprotein IIb/IIIa (α IIb β 3 ) on Platelets Upregulates CD40L and Triggers CD40L-Dependent Matrix Degradation by Endothelial Cells

“…23 Consistent with our data, CD40L-expressing T-cell membranes have been shown to enhance endothelial secretion of both pro-MMP-9 and activated MMP-2 in vitro. 16 Recently, it was shown that platelets enhance the release of soluble uPAR by endothelial cells; however, the underlying mechanism remained unclear. 24 Our data present evidence that platelets can induce matrix-degrading activity in HUVEC via platelet-associated CD40L and that this mechanism is regulated by GP IIb/IIIa, a receptor involved substantially in platelet-endothelial interaction.…”

“…13 MMP-2-specific and MMP-9 -specific gelatinolytic activity was studied by SDS-PAGE zymography 15 using supernatants of cells that were kept under serum-free conditions 24 hours before the experiments, as described elsewhere. 16 …”

CD40-dependent Activation of Phosphatidylinositol 3-Kinase/Akt Pathway Mediates Endothelial Cell Survival and in Vitro Angiogenesis

“…Blockade of CD40-CD154 interaction in atherosclerosis was found not only to diminish the formation and progression of mouse atheroma but also to foster changes in lesions associated with plaque destabilization (16,17). Recently, it has also been shown that the engagement of CD40 on endothelial cells by CD154 induces in vitro vessel-like tubule formation and expression of matrix metalloproteinases, two events involved in neovascularization (18). In vivo, the stimulation of CD40 triggered neoangiogenesis in mice (6,19).…”