IntroductionAngiogenesis, the formation of new blood vessels from a preexisting vascular bed, is a pivotal process not only in embryonic development but also in the progression of a variety of pathologic conditions. 1 A large number of molecules, which are composed of growth factors, cytokines, and lipid metabolites, are shown to be involved in pathophysiologic neovascularization by stimulating endothelial cells (ECs) directly or indirectly. 2 Some of these factors, including VEGF, often possess their abilities to increase vascular permeability and thus contribute to deteriorating tissue damage.Receptor activator of nuclear factor (NF)-B ligand (RANKL), also known as ODF, TRANCE, and OPGL, has well-understood roles in the skeletal and immune systems in which it induces osteoclast differentiation from hematopoietic precursors and regulates the function and survival of dendritic cells. 3 Recently, interest has grown in its physiologic and pathologic relevance to vascular biology. 4 Mounting evidence suggests that RANKL and its decoy receptor, osteoprotegrin (OPG), participate in multiple aspects of vascular calcification; for example, mice lacking OPG suffer late medial calcification of the renal and aortic arteries in addition to early onset osteoporosis. [5][6][7] Moreover, a role for the OPG/RANKL/ RANK axis in atherogenesis and plaque destabilization has been recently reported. 8 OPG inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE Ϫ/Ϫ mice. 9 TRANCE is strongly expressed in vascular cells in vitro, as well as in vivo. OPG and it are induced by inflammatory cytokines in human ECs, although with different temporal profiles. 10 In vivo, RANKL is present in the small blood vessels of the skin and in arterial smooth muscle cells, 11 and it appears to be up-regulated in atherosclerotic lesions, calcified vessels, and valves. 4,6,9 Moreover, the RANKL receptor, RANK, is also expressed in ECs of the rat coronary artery and developing blood vessels of the rat embryo in vivo, as well as in freshly isolated human umbilical vein ECs (HUVECs). 12 In agreement with these patterns of expression, RANKL stimulates the survival of cultured ECs and their production of inflammatory cell adhesion molecules; it also promotes in vitro angiogenesis by the ECs and elicits neoangiogenesis in animal models. 13 Moreover, VEGF increases RANK mRNA and protein in ECs, augmenting their angiogenic response to RANKL. 12 Therefore, the RANKL/RANK/OPG system is believed to be an important link between the vascular, skeletal, and immune systems.Endothelium-derived nitric oxide (NO), originally identified as endothelium-derived relaxing factor, promotes angiogenesis and plays an important role in vascular remodeling and the maintenance of vascular integrity. 14,15 In ECs, NO is a product of the An Inside Blood analysis of this article appears at the front of this issue.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact,...

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