Broussonetia kazinoki modulates the expression of VEGFR-2 and MMP-2 through the inhibition of ERK, Akt and p70S6K-dependent signaling pathways: Its implication in endothelial cell proliferation, migration and tubular formation

Abstract

Broussonetia kazinoki (BK) has been used as a traditional medicine to improve vision, as well as for inflammatory and infectious diseases. In the present study, we investigated the effects and molecular mechanism of the ethanolic extract of BK on cell proliferation, migration and tubular formation in vascular endothelial growth factor-A (VEGF-A)-treated human umbilical vein endothelial cells. BK treatment inhibited VEGF-A-stimulated endothelial cell proliferation through the downregulation of cell cycle-related proteins including cyclin-dependent kinases and cyclins. Moreover, BK treatment suppressed cell migration and tubular formation in response to VEGF-A. These anti-angiogenic activities of BK were associated with the inactivation of mitogenic signaling pathways including extracellular signal-regulated kinase, Akt and p70S6K, and the subsequent downregulation of VEGFR-2 and matrix metalloproteinase-2. Taken together, these findings suggest further evaluation and development of BK as a potential therapeutic agent for the treatment and prevention of angiogenesis-related diseases including cancer.

The Role of the Y Box Binding Protein 1 C-Terminal Domain in Vascular Endothelial Cell Proliferation, Apoptosis, and Angiogenesis

“…Many proangiogenic factors (such as vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]) control the angiogenesis process. The ERK signaling pathway is reported to participate in VEGF-and FGF-induced endothelial cell migration and tube formation (Tong et al, 2013;Cho et al, 2014) and abrogating of ERK activation contributes to the prevention of angiogenesis-related diseases, including cancer. The current study demonstrated that YB1 CTD downregulated the phospho-ERK level in EA.hy926 endothelial cells, which may mediate YB1 CTD-inhibited tube formation and antiangiogenesis.…”

STAT3-mediated MMP-2 expression is required for 15-HETE-induced vascular adventitial fibroblast migration

“…Several lines of evidence suggest a role for MMP-2 in regulation of cell migration and proliferation [25,26]. To examine whether MMP-2 is activated by 15-HETE in VAFs, we performed Western blot analysis.…”

“…Excessive or inappropriate expression of MMP expression may contribute to the pathogenesis of tissue-destructive processes in a wide variety of diseases, including pulmonary hypertension [11]. Matrix metalloproteinase-2 (MMP-2) is expressed ubiquitously in various cell types including cardiomyocytes, endothelial cells, fibroblasts, and vascular smooth muscle cells and plays a crucial role in angiogenesis regulation [12][13][14]. MMP-2 and -9 are important players in several cardiovascular diseases including atherosclerosis, ischemic heart disease, and heart failure [15][16][17].…”

Recombinant canstatin inhibits VEGF‐A‐induced lymphangiogenesis and metastasis in an oral squamous cell carcinoma SCC‐VII animal model

“…). VEGF‐A stimulates the expression of VEGFR‐2 in HUVECs, which is mediated by the VEGF‐A‐stimulated activation of extracellular signaling‐regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3‐kinase (PI3K)/Akt signaling . Recombinant canstatin decreased the phosphorylation of ERK1/2, PI3K, and Akt stimulated by VEGF‐A in HLMECs (data not shown).…”