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Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2553-61. doi: 10.1161/ATVBAHA.110.214999. Epub 2010 Sep 23.

Functional analyses of the bone marrow kinase in the X chromosome in vascular endothelial growth factor-induced lymphangiogenesis.

Author information

1
Department of Pathology, Yale University School of Medicine, New Haven, Conn 06520, USA.

Abstract

OBJECTIVE:

The goal of this study was to investigate the novel hypothesis that bone marrow kinase in the X chromosome (Bmx), an established inflammatory mediator of pathological angiogenesis, promotes lymphangiogenesis.

METHODS AND RESULTS:

We have recently demonstrated a critical role for Bmx in inflammatory angiogenesis. However, the role of Bmx in lymphangiogenesis has not been investigated. Here, we show that in wild-type mice, Bmx is upregulated in lymphatic vessels in response to vascular endothelial growth factor (VEGF). In comparison with wild-type mice, Bmx-deficient mice mount weaker lymphangiogenic responses to VEGF-A and VEGF-C in 2 mouse models. In vitro, Bmx is expressed in cultured human dermal microvascular lymphatic endothelial cells. Furthermore, pharmacological inhibition and short interfering RNA mediated silencing of Bmx reduces VEGF-A and VEGF-C-induced signaling and lymphatic endothelial cell tube formation. Mechanistically, we demonstrated that Bmx differentially regulates VEGFR-2 and VEGFR-3 receptor signaling pathways: Bmx associates with and directly regulates VEGFR-2 activation, whereas Bmx associates with VEGFR-3 and regulates downstream signaling without an effect on the receptor autophosphorylation.

CONCLUSIONS:

Our in vivo and in vitro results provide the first insight into the mechanism by which Bmx mediates VEGF-dependent lymphangiogenic signaling.

PMID:
20864667
PMCID:
PMC3106279
DOI:
10.1161/ATVBAHA.110.214999
[Indexed for MEDLINE]
Free PMC Article

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