Angiogenic Role of LYVE-1–Positive Macrophages in Adipose Tissue

Abstract

Abstract-Here we report the discovery of a characteristic dense vascular network (DVN) in the tip portion of epididymal adipose tissue in adult mice. The DVN is formed by angiogenesis rather than by vasculogenesis, and has functional blood circulation. This DVN and its subsequent branching may provide a new functional route for adipogenesis. The recruitment, infiltration, and accumulation of bone marrow-derived LYVE-1 ϩ macrophages in the tip region are crucial for the formation of the DVN. Matrix metalloproteinases (MMPs) and the VEGF-VEGFR2 system are responsible not only for the formation of the DVN, but also for the recruitment and infiltration of LYVE-1 ϩ macrophages into the epididymal adipose tissue tip region. SDF-1, but not the MCP-1-CCR2 system, is a critical factor in recruitment and ongoing retention of macrophages in this area. We also demonstrate that the tip region of epididymal adipose tissue is highly hypoxic, and thus provides a microenvironment conducive to the high expression and enhanced activities of VEGF, VEGFR2, MMPs, and SDF-1 in autocrine and paracrine manners, to create an ideal niche for the recruitment, retention, and angiogenic action of macrophages. These findings shed light on the complex interplay between macrophage infiltration, angiogenesis, and adipogenesis in the tip region of adult epididymal adipose tissue, and provide novel insight into the regulation of alternative outgrowth of adipose tissue. (Circ Res. 2007;100:e47-e57.) Key Words: adipogenesis Ⅲ angiogenesis Ⅲ lymphatic vessel hyaluronan receptor 1 Ⅲ macrophages Ⅲ matrix metalloproteinases Ⅲ monocyte chemoattractant protein-1 Ⅲ vascular endothelial growth factor receptors A dipose tissue is a unique organ that has reversible growth depending on the balance of fat metabolism. 1 It is mainly composed of adipocytes supported by stromalvascular tissue, which contains vascular endothelial cells, macrophages, and poorly characterized stem cells. [2][3][4] Developmental growth of adipocytes through adipogenesis (defined as development of adipoblasts into differentiated adipocytes) is accompanied by the growth of vasculature in adipose tissue. 2,3 Recent studies using pharmacological agents or cell implantation have proposed that the growth of adipose tissue is angiogenesis-dependent. [5][6][7][8] However, little is known about the nature of how angiogenesis governs the growth of adipose tissue and, inversely, how the growth of adipose tissue affects the growth of vasculature.Macrophages are released from the bone marrow as immature monocytes and circulate in the blood before extravasation into their target tissues, where they differentiate into resident macrophages. Thus, macrophages are found in every tissue of the body and, depending on the local microenvironment, acquire specialized functions including phagocytosis, antigen presentation, tissue remodeling, and the secretion of a wide range of growth factors and cytokines. 9 The distribution and accumulation of macrophages in certain tissue are mediated by several CC chemok...

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