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

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

SUBMITTER: Jones D

PROVIDER: S-EPMC3106279 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

Jones Dennis D Xu Zhe Z Zhang Haifeng H He Yun Y Kluger Martin S MS Chen Hong H Min Wang W

Arteriosclerosis, thrombosis, and vascular biology 20100923 12

<h4>Objective</h4>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.<h4>Methods and results</h4>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 ...[more]

PMID: 20864667

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Project description:: Chondrogenic differentiation of bone marrow-derived mesenchymal stromal/stem cells (MSCs) can be induced by presenting morphogenetic factors or soluble signals but typically suffers from limited efficiency, reproducibility across primary batches, and maintenance of phenotypic stability. Considering the avascular and hypoxic milieu of articular cartilage, we hypothesized that sole inhibition of angiogenesis can provide physiological cues to direct in vivo differentiation of uncommitted MSCs to stable cartilage formation. Human MSCs were retrovirally transduced to express a decoy soluble vascular endothelial growth factor (VEGF) receptor-2 (sFlk1), which efficiently sequesters endogenous VEGF in vivo, seeded on collagen sponges and immediately implanted ectopically in nude mice. Although naïve cells formed vascularized fibrous tissue, sFlk1-MSCs abolished vascular ingrowth into engineered constructs, which efficiently and reproducibly developed into hyaline cartilage. The generated cartilage was phenotypically stable and showed no sign of hypertrophic evolution up to 12 weeks. In vitro analyses indicated that spontaneous chondrogenic differentiation by blockade of angiogenesis was related to the generation of a hypoxic environment, in turn activating the transforming growth factor-? pathway. These findings suggest that VEGF blockade is a robust strategy to enhance cartilage repair by endogenous or grafted mesenchymal progenitors. This article outlines the general paradigm of controlling the fate of implanted stem/progenitor cells by engineering their ability to establish specific microenvironmental conditions rather than directly providing individual morphogenic cues.SignificanceChondrogenic differentiation of mesenchymal stromal/stem cells (MSCs) is typically targeted by morphogen delivery, which is often associated with limited efficiency, stability, and robustness. This article proposes a strategy to engineer MSCs with the capacity to establish specific microenvironmental conditions, supporting their own targeted differentiation program. Sole blockade of angiogenesis mediated by transduction for sFlk-1, without delivery of additional morphogens, is sufficient for inducing MSC chondrogenic differentiation. The findings represent a relevant step forward in the field because the method allowed reducing interdonor variability in MSC differentiation efficiency and, importantly, onset of a stable, nonhypertrophic chondrocyte phenotype.

Dataset Information

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

Publications

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

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