Hypoxia increases Annexin A2 expression in osteoblastic cells via VEGF and ERK

Genetos, Damian C.; Wong, Alice; Watari, Shinya; Yellowley, Clare E.

doi:10.1016/j.bone.2010.08.024

Cited by 42 publications

(32 citation statements)

References 61 publications

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“…In isolated RMVECs exposed to hypoxic conditions, an upregulation in the cell-surface and intracellular levels of AnxA2 was observed followed by a concomitant increase in the cellsurface levels of the AnxA2-tPA complex. These results are supported by previous observations that suggest that AnxA2 is upregulated in VEGF-mediated neovascular responses in response to hypoxia (Genetos et al, 2010;Zhao et al, 2009). Under hypoxia, both VEGF and AnxA2 are upregulated by hypoxia-inducible factor 1 alpha (HIF-1) thereby potentiating ischemia-induced neovascularization (Genetos et al, 2010).…”

Section: Discussionsupporting

confidence: 90%

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

Valapala

Thamake

Vishwanatha

2011

Journal of Cell Science

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SummaryExtracellular proteolysis is an indispensable requirement for the formation of new blood vessels during neovascularization and is implicated in the generation of several angiogenic regulatory molecules. Anti-proteolytic agents have become attractive therapeutic strategies in diseases associated with excessive neovascularization. Annexin A2 (AnxA2) is an endothelial cell-surface receptor for the generation of active proteolytic factors, such as plasmin. Here, we show that AnxA2 is abundantly expressed in the neovascular tufts in a murine model of neovascularization. Exposure to hypoxic conditions results in elevation of AnxA2 and tissue plasminogen activator (tPA) in human retinal microvascular endothelial cells (RMVECs). We show that the hexapeptide competitive inhibitor LCKLSL, which targets the N-terminal tPA-binding site of AnxA2, binds efficiently to cell-surface AnxA2 compared with binding of the control peptide LGKLSL. Treatment with the competitive peptide inhibits the generation of plasmin and suppresses the VEGFinduced activity of tPA under hypoxic conditions. Application of the competitive peptide in two in vivo models of angiogenesis demonstrated suppression of the angiogenic responses, which was also associated with significant changes in the vascular sprouting. These results suggest that AnxA2-mediated plasmin generation is an important event in angiogenesis and is inhibited by a specific competitive peptide that inhibits the binding of tPA to AnxA2.

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Section: Discussionsupporting

confidence: 90%

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

Valapala

Thamake

Vishwanatha

2011

Journal of Cell Science

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“…And apoptosis in osteoblast cells have been widely accepted as a severe response to hypoxia. [33][34][35] We next investigated the role of microRNA-210 in the hypoxia-induced apoptosis in MG-63 cells. It was demonstrated that less MG-63 cells post-microRNA-210 mimics transfection developed apoptosis, and expressed the apoptosis-execution caspase, caspase 3 and caspase 9.…”

Section: Discussionmentioning

confidence: 99%

“…[33][34][35] It is the inhibition of the electron transport chain at the inner membrane of the mitochondria which is the most direct induction of hypoxia-induced apoptosis. Firstly, the sensitivity of MG-63 osteoblast cells to 5-FU was measured.…”

Section: Microrna-210 Mimics Reduces the 5-fu-caused Death And Promotmentioning

confidence: 99%

HIF-1α-induced microRNA-210 reduces hypoxia-induced osteoblast MG-63 cell apoptosis

Sun

Peng

2015

Bioscience, Biotechnology, and Biochemistry

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To better understand the ischemic-hypoxia-induced fracture healing impairment, we determined in this study the microRNA-210 expression in broken bone specimens and in osteoblasts under hypoxia and then determined the influence of microRNA-210 overexpression on the osteoblast cell proliferation and apoptosis. Results demonstrated that microRNA-210 expression was upregulated with an association with HIF-1α overexpression in clinical human catagmatic tissues and was upregulated HIF-1α-dependently in response to hypoxia in osteoblast MG-63 cells. CCK-8 assay indicated that microRNA-210 upregulation by microRNA-210 mimics reduced the chemotherapeutic 5-FU-induced osteoblast cell death, and colony formation assay demonstrated that microRNA-210 mimics promoted osteoblast cells growth. Moreover, the microRNA-210 mimics transfection inhibited the hypoxia-induced MG-63 cell apoptosis via inhibiting the activation of caspase 3 and caspase 9. Therefore, our research indicated a protective role of microRNA-210 in response to hypoxia. And microRNA-210 might serve as a protective role in bone fracture healing.

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“…VEGF-related drugs have been used in clinical applications [8]. Over the past several decades, work from several laboratories has shown that annexin A2 plays an important role in NV by interacting with VEGF [9, 10]. Furthermore, work on annexin A2/AX2R in regulation of NV has been reported.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Krüppel-Like Transcription Factor 2

Guo

Song

Zhao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Annexin A2 receptor (AX2R) can mediate annexin A2 signalling and induce apoptosis in a variety of cells, but its role in neovascularization (NV) remains unclear. Krüppel-like transcription factor 2 (KLF2) is known to be expressed in a range of cell types and to participate in a number of processes during development and disease, such as endothelial homeostasis, vasoregulation and vascular growth/remodelling. The aim of our study was to investigate the role of AX2R in NV and the plausible molecular mechanism. Methods: We constructed a eukaryotic overexpression plasmid for AX2R (Lenti-AX2R) by using polymerase chain reaction (PCR). The full-length human AX2R gene was transfected into human retinal endothelial cells (HRECs) and human umbilical vein endothelial cells (HUVECs) using lentivirus vectors to overexpress AX2R. All experiments were divided into three groups: control, negative control (Lenti-EGFP), and Lenti-AX2R.Cell proliferation, cell migration, tube formation, mouse aortic ring assays and mouse matrigel plug assay were applied to analyse the effect of AX2R in NV. Furthermore, we conducted flow cytometry to evaluate whether AX2R could influence the cell cycle. A series of cell cycle-related proteins including cyclin A1, cyclin B1, cyclin D1, cyclin E1, CDK1, and p-CDC2 were detected by WB. The mRNA and protein levels of KLF2, vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) were further quantified by RT-PCR and WB to reveal the possible mechanism. Results: Overexpression of AX2R significantly inhibited cell proliferation, migration and tube formation in both types of endothelial cells (ECs), HRECs and HUVECs. It also suppressed vessel sprouting in the mouse aortic ring assay and NV in mouse matrigel plug assay. Furthermore, infection with Lenti-AX2R lentivirus arrested the cell cycle in S/G2 and influenced the expression of a series of cell cycle-related proteins. We also found that the overexpression of AX2R increased the expression of KLF2, mediating VEGF and VEGFR2. Conclusions: Overexpression of AX2R contributes to the inhibition of NV via suppressing KLF2 ubiquitin-dependent protein degradation, which might therefore be a therapeutic option for NV. It could be considered more broadly as an anti-angiogenic agent in the treatment of neovascular-related diseases in the future.

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Hypoxia increases Annexin A2 expression in osteoblastic cells via VEGF and ERK

Cited by 42 publications

References 61 publications

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

A competitive hexapeptide inhibitor of annexin A2 prevents hypoxia-induced angiogenic events

HIF-1α-induced microRNA-210 reduces hypoxia-induced osteoblast MG-63 cell apoptosis

Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Krüppel-Like Transcription Factor 2

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