Regulation of collateral blood vessel development by the innate and adaptive immune system Andrea la Sala 1 , Laura Pontecorvo 1 , Alessia Agresta 2 , Giuseppe Rosano 3 and Eugenio Stabile 2 1 Laboratory of Molecular and Cellular Immunology, IRCCS San Raffaele Pisana, 00166 Rome, Italy 2 Centro Polidiagnostico Stabile, 84122 Salerno, Italy 3 San Raffaele Sulmona, 67039 Sulmona, Italy The development of collateral circulation is an inherent compensatory mechanism to restore impaired blood perfusion following artery stenosis and/or occlusion. This process, termed arteriogenesis, is driven by inflam- mation and involves a complex remodeling of pre-exist- ing conduit vessels running in parallel to the occluded artery. Recent studies have unveiled roles for different immune cell subsets as regulators of arteriogenesis, including natural killer (NK) cells, T helper 17 (Th17) cells, regulatory T lymphocytes (Tregs), and functional subsets of macrophages (e.g., M2 macrophages). This review summarizes recent findings and discusses future research needed to better define the time during which each cellular subset is active and reveal further critical regulatory switches. Arteriogenesis versus angiogenesis Postnatal vessel growth occurs following two distinct pro- cesses, angiogenesis and arteriogenesis. Angiogenesis involves sprouting new blood vessels from pre-existing ones, providing O 2 and nutrients, and allowing tissues to discharge metabolic products. Angiogenesis is quickly trig- gered in response to hypoxic or ischemic conditions and results in a reduced average distance between cells and the nearest capillary, thus improving oxygen delivery. Howev- er, an increase in the number of capillaries without a concomitant increase in the number of conducting vessels results in an overall increment of resistance and is insuffi- cient to improve tissue perfusion. Arteriogenesis is not driven by ischemia, however, it occurs in response to increased fluid shear stress, often as a consequence of vessel occlusion, and describes the remodeling and growth of collateral arterioles (or collaterals) from pre-existing anastomoses. Consequently, the blood flow downstream of the site of vessel occlusion is recovered. Thus, the differences between angiogenesis and arterio- genesis are in the triggering stimulus (ischemia versus shear stress), the growth mechanism involved, and the result. Although capillaries are structurally simple tubes made of endothelial cells, with no additional wall structures, arteriogenesis implies a complex process that includes co- ordinated proliferation of endothelial and smooth muscle cells, as well as fibroblasts, accompanied by extensive tissue remodeling. Figure 1 outlines the anatomical structures of arteries, arterioles, and capillaries. Collaterals originate, at least in part, from pre-existing vessels proximal to the site of arterial obstruction and, therefore, located proximally to the ischemic tissue [1,2]. Although relatively little blood flow occurs in these vessels under normal conditions (Figure 2a), pressure gradients created by the distal obstruction promote their opening and the establishment of flow. The increase in blood flow Review Glossary Anastomoses: connection of two previously branched out blood vessels. Arteriogenesis: process leading to the increase in caliber of pre-existing conduit vessels (arteries or arterioles). Arteriogenesis is thought to be the result of inflammation, which in turn is initiated by the activation of endothelial cells due to increased shear forces and consequent recruitment of leukocytes. Arteriole: small branch of an artery that connects to capillaries. Bone marrow chimera: the bone marrow chimeric mouse is obtained by the transfer of bone marrow isolated from a donor mouse into an irradiated recipient with a different genetic background. The recipient mouse will be identical to its littermates except that bone marrow-derived cells will carry genetic characteristics of the donor. CCL2: known as monocyte chemotactic protein-1 (MCP-1), belongs to the CC chemokine family. It is produced primarily by monocytes, macrophages, and dendritic cells. Upon binding to CC chemokine receptors CCR2 and CCR4, it induces chemotaxis in monocytes and basophils. Ischemia: a condition of insufficient blood supply to an anatomical region. M1 macrophages: the conventional macrophage population that is activated by Toll-like receptors (TLRs) and by interferon-g (IFN-g), and which exert phagocytic and microbicidal activities by synthesizing oxygen radicals. M2 macrophages: a specialized subset of macrophages that express arginase 1, mannose receptor CD206, IL-4 receptor alpha chain under the stimulation of IL-4 or IL-13 and promote angiogenesis. Perfusion: process of delivering blood to a tissue through the network of blood vessels. Tissue perfusion is the volume of blood that flows through a given quantity of tissue and is expressed as ml of blood/100 g of tissue. Regulatory T cells (Tregs): T lymphocytes that suppress the activity of lymphocytes and dendritic cells. Although by definition regulatory T cells belong to the CD4 + cell subset, CD8 + T cells with similar properties have been identified. Shear stress: the force imposed on the endothelium in a vessel by the movement of the flowing blood. T helper lymphocytes: subset of T lymphocytes expressing CD4 that help B cells produce antibodies and secrete cytokines and chemokines that stimulate both humoral and cell-mediated immune responses. Toll-like receptors: family of receptors that recognize molecular patterns associated with pathogenic organisms, such as bacteria and viruses, or injured host tissues. Corresponding author: la Sala, A. (andrea.lasala@sanraffaele.it) Keywords: arteriogenesis; T helper lymphocytes; regulatory T cells; macrophages; collateral vessel growth; ischemia.. 494 1471-4914/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2012.06.007 Trends in Molecular Medicine, August 2012, Vol. 18, No. 8