Receptor activator of nuclear factor (NF)-κB ligand (RANKL) increases vascular permeability: Impaired permeability and angiogenesis in eNOS-deficient mice

Jeong Ki Min, Young Lai Cho, Jae Hoon Choi, Yonghak Kim, Hun Kim Jeong, Suk Yu Young, Jaerang Rho, Naoki Mochizuki, Young Myeong Kim, Taeg Oh Goo, Young Guen Kwon

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Abstract

Receptor activator of nuclear factor (NF)-κB 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.

Original languageEnglish
Pages (from-to)1495-1502
Number of pages8
JournalBlood
Volume109
Issue number4
DOIs
Publication statusPublished - 2007 Feb 15

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Min, J. K., Cho, Y. L., Choi, J. H., Kim, Y., Jeong, H. K., Young, S. Y., Rho, J., Mochizuki, N., Kim, Y. M., Goo, T. O., & Kwon, Y. G. (2007). Receptor activator of nuclear factor (NF)-κB ligand (RANKL) increases vascular permeability: Impaired permeability and angiogenesis in eNOS-deficient mice. Blood, 109(4), 1495-1502. https://doi.org/10.1182/blood-2006-06-029298