Dendritic cell–endothelial cell cross-talk in angiogenesis Silvano Sozzani, Marco Rusnati, Elena Riboldi, Stefania Mitola and Marco Presta Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Viale Europa 11, 25123 Brescia, Italy Dendritic cells (DCs) are professional antigen-presenting cells that have a pivotal role in the onset and regulation of adaptive immune responses. DCs have the ability to regulate inflammation through their capacity to release cytokines and chemokines and kill pathogens, which they share with other phagocytes. Recent observations have shown that different DC subsets produce and release various pro- and anti-angiogenic mediators depending on their activation status and cytokine milieu. In particular, alternatively activated DCs exert a potent pro-angiogenic activity that is mediated by the proto- typic angiogenic growth factor vascular endothelial growth factor-A (VEGF-A). In turn, pro- and anti-angio- genic mediators can affect the biology of DCs, modulat- ing their differentiation and maturation. Finally, DCs can trans-differentiate into endothelial-like cells, possibly contributing to vasculogenesis in the adult. Thus, DCs might exert an important impact on the neovasculariza- tion process in different physiopathological conditions. The process of neovascularization In the embryo, endothelial and hematopoietic lineages arise from a common mesodermal progenitor, the heman- gioblast [1]. The formation of the embryonic blood vascular system originates from the assembly of endothelial pre- cursors to form a vascular plexus (a mechanism known as vasculogenesis). Then, the vascular network expands by angiogenesis, the process of formation of new blood vessels from pre-existing ones [2]. Angiogenesis begins with the degradation of the basement membrane by activated endo- thelial cells (ECs) that migrate and proliferate, leading to the formation of solid EC sprouts into the stromal space. Vascular loops are then formed and capillary tubes develop with the formation of tight junctions and deposition of new basement membrane. In the adult, angiogenesis has a key role in the female reproductive system and in various pathological conditions, including wound repair, tumor growth and inflammation [2]. Numerous angiogenic growth factors have been identified, including members of the vascular endothelial growth factor (VEGF) family, hepatocyte growth factor (HGF), angiopoietins, angiogenin, endothelin-1 (ET-1), transforming growth factor (TGF)-a and -b, platelet-derived growth factor, tumor necrosis factor (TNF)-a, interleukins (ILs), certain CXC chemokines, midkine and pleiotrophin and members of the fibroblast growth factor (FGF) family. Their action is counteracted by a variety of endogenous angiogenesis inhibitors [3]. The local release of angiogenic growth factors and/or the down-regulation of natural angio- genic inhibitors, with a consequent alteration of the angio- genic balance, are responsible for the activation of the process of neovascularization. In the adult, human peripheral blood contains bone-marrow-derived endothelial progenitor cells (EPCs) with vasculogenic properties that complement angiogen- esis afforded by the pre-existing endothelium. EPCs might derive from CD34 + as well as CD34 À cells and contribute to new blood vessel formation after neoplastic transform- ation, limb ischemia, atherosclerosis or myocardial infarc- tion [4]. Interestingly, various angiogenic growth factors (e.g. VEGF-A), pro-angiogenic cytokines [e.g. granulocyte– macrophage colony-stimulating factor (GM-CSF)] and che- mokines (e.g. CXCL12) are also able to recruit vasculogenic EC precursors during neovascularization [4]. Relevant to the cross-talk between myeloid cells and endothelium during angiogenesis, comobilization of VEGF receptor-1 (VEGFR-1) + myeloid cells and VEGFR-2 + EPCs might facilitate neovascularization [4]. Stromal and inflammatory cells, including T lymphocytes, mast cells, neutrophils, monocytes and hema- topoietic precursors, might contribute to the modulation of angiogenesis or vasculogenesis by the production of pro- and anti-angiogenic mediators and/or by their trans-differen- tiation into endothelial-like cells. Here, we describe and discuss recent observations about the DC–EC cross-talk during neovascularization. DCs produce pro- and anti-angiogenic mediators DCs are bone-marrow-, haematopoietic-derived, professional antigen-presenting cells (APCs) with a unique ability to induce both primary and secondary T- and B-cell responses as well as immune tolerance [5,6]. DCs reside in an immature state in peripheral tissues where they exert a sentinel function for incoming antigens. On microbial con- tact and stimulation by inflammatory cytokines, DCs ingest antigens, undergo a process of maturation and traffic through the afferent lymphatics into the T-cell area of the draining lymph node to initiate immune responses [7]. DCs are a heterogeneous population in terms of origin, morphology, phenotype and functions [8]. In both mice and humans, at least two major subsets of DC are present, namely conventional myeloid DCs and plasmacytoid DCs. In the peripheral blood, conventional DC precursors are Review TRENDS in Immunology Vol.28 No.9 Corresponding author: Sozzani, S. (sozzani@med.unibs.it). Available online 10 August 2007. www.sciencedirect.com 1471-4906/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2007.07.006