Abstract
Angiogenesis is an essential step for many physiological and pathological processes. Tumor necrosis factor (TNF) superfamily cytokines are increasingly recognized as key modulators of angiogenesis. In this study, we tested whether TNF-related activation-induced cytokine (TRANCE), a new member of the TNF superfamily, possesses angiogenic activity in vitro and in vivo. TRANCE stimulated DNA synthesis, chemotactic motility, and capillary-like tube formation in primary cultured human umbilical vein endothelial cells (HUVECs). Both Matrigel plug assay in mice and chick chorioallantoic membrane assay revealed that TRANCE potently induced neovascularization in vivo. TRANCE had no effect on vascular endothelial growth factor (VEGF) expression in HUVECs and TRANCE-induced angiogenic activity was not suppressed by VEGF-neutralizing antibody, implying that TRANCE-induced angiogenesis may be the result of its direct action on endothelial cells. TRANCE evoked a time- and dose-dependent activation of the mitogen-activated protein kinases ERK1/2 and focal adhesion kinase p125(FAK) in HUVECs, which are closely linked to angiogenesis. These signaling events were blocked by the Src inhibitor PP1 or the phospholipase C (PLC) inhibitor. Furthermore, these inhibitors and the Ca(2+) chelator BAPTA-AM suppressed TRANCE-induced HUVEC migration. These results indicate that the angiogenic activity of TRANCE is mediated through the Src-PLC-Ca(2+) signaling cascade upon receptor engagement in endothelial cells, suggesting the role of TRANCE in neovessel formation under physiological and pathological conditions.
Highlights
Angiogenesis, the formation of new blood vessels from preexisting endothelium, is a fundamental step in a variety of
Positive regulators of angiogenesis are classified into two groups: direct inducers, such as vascular endothelial growth factor (VEGF)1 and bFGF that can induce proliferation, migration, and morphogenesis of endothelial cells and indirect inducers that act on endothelial cells via production of direct angiogenic factors from accessory cells such as immune cells and tumor cells [4]
Pretreatment of human umbilical vein endothelial cells (HUVECs) with PP1, an inhibitor for Src family kinases, completely blocked both extracellular signal-regulated kinase (ERK) and p125FAK activation by TNF-related activation-induced cytokine (TRANCE) (Fig. 6). These results indicate that Src family tyrosine kinases lie upstream of the ERK and p125FAK cascades initiated by the TRANCE receptor in HUVECs. c-Src is previously shown to interact with RANK upon receptor engagement, and the resulting activation of c-Src is responsible for TRANCE-induced cell survival in dendritic cells [16]
Summary
Angiogenesis, the formation of new blood vessels from preexisting endothelium, is a fundamental step in a variety of. Positive regulators of angiogenesis are classified into two groups: direct inducers, such as vascular endothelial growth factor (VEGF) and bFGF that can induce proliferation, migration, and morphogenesis of endothelial cells and indirect inducers that act on endothelial cells via production of direct angiogenic factors from accessory cells such as immune cells and tumor cells [4]. It has been reported that, in a T cell-dependent model of rat adjuvant arthritis, TRANCE regulates bone loss and cartilage destruction [13]. These effects of TRANCE are exerted by its binding to the transmembrane receptor RANK (receptor activator of NF-B). The vasculature is crucial for the processes of bone formation by paving the way for a variety of cells essential for bone morphogenesis, including osteoblasts, to migrate into cartilage.
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