T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism - Implications for tubule formation

Neovascularization frequently accompanies chronic immune responses characte rized by T cell infiltration and activation. Angiogenesis requires endothel ial cells (ECs) to penetrate extracellular matrix, a process that involves matric; metalloproteinases (MMPs). We report here that activated human T ce lls mediate contact-dependent expression of MMPs in ECs through CD40/CD40 l igand signaling. Ligation of CD40 on ECs induced ne novo expression of gela tinase B (MMP-9), increased interstitial collagenase (MMP-1) and stromelysi n (MMP-3), and activated gelatinase A (MMP-2). Recombinant human CD40L indu ced expression of MMPs by human vascular ECs to a greater extent than did m aximally effective concentrations of interleukin-1 beta or tumor necrosis f actor-alpha. Moreover, activation of human vascular ECs through CD40 induce d 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 an d promoted an angiogenic function of ECs via CD40L-CD40 signaling. As vascu lar cells at the sites of chronic inflammation, such as atherosclerotic pla ques, express CD40 and its ligand, our findings suggest that ligation of CD 40 on ECs can mediate aspects of vascular remodeling and neovessel formatio n during atherogenesis and other chronic immune reactions.