title: Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) increases vascular permeability: impaired permeability and angiogenesis in eNOS-deficient mice.
abstract: Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) is emerging as an important regulator of vascular pathophysiology. Here, we demonstrate a novel role of RANKL as a vascular permeability factor and a critical role of endothelial nitric oxide synthase (eNOS) in RANKL-induced endothelial function. RANKL increased the vascular permeability and leukocyte infiltration in vivo and caused the breakdown of the blood-retinal barrier in wild-type mice but not in eNOS-deficient mice. In vitro, it increased endothelial permeability and reduced VE-cadherin-facilitated endothelial cell-cell junctions in a NO-dependent manner. RANKL also led to the activation of Akt and eNOS and to NO production in endothelial cells (ECs). These effects were suppressed by the inhibition of TRAF6, phosphoinositide 3'-kinase (PI3K), Akt, or NOS by genetic or pharmacologic means. Inhibition of the TRAF6-mediated NO pathway reduced EC migration and capillary-like tube formation in response to RANKL. Moreover, the effects of RANKL on ECs sprouting from the aorta, and neovessel formation in both the mouse Matrigel plug assay and corneal micropocket assay, were impaired in eNOS-deficient mice. These results demonstrate that RANKL promotes vascular permeability and angiogenesis by stimulating eNOS by a TRAF6-PI3K-Akt-dependent mechanism. These properties may be relevant to the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases.
authors.affiliation: Department of Biochemistry, College of Sciences, Yonsei University, and Department of Ophthalmology, Seoul National University Hospital, Republic of Korea.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.forename: Young-Lai
authors.initials: YL
authors.lastname: Cho
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: Yonghak
authors.initials: Y
authors.lastname: Kim
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Yu
authors.forename: Jaerang
authors.initials: J
authors.lastname: Rho
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D007365:Intercellular Junctions / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; C505688:TNFSF11 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt