scholarly journals Pro-Angiogenic Effects of Resveratrol in Brain Endothelial Cells: Nitric Oxide-Mediated Regulation of Vascular Endothelial Growth Factor and Metalloproteinases

2012 ◽  
Vol 32 (5) ◽  
pp. 884-895 ◽  
Author(s):  
Fabricio Simão ◽  
Aline S Pagnussat ◽  
Ji Hae Seo ◽  
Deepti Navaratna ◽  
Wendy Leung ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Vascular Endothelial ◽  
Cerebral Endothelial Cells ◽  
Endothelial Growth Factor

Resveratrol may be a powerful way of protecting the brain against a wide variety of stress and injury. Recently, it has been proposed that resveratrol not only reduces brain injury but also promotes recovery after stroke. But the underlying mechanisms are unclear. Here, we tested the hypothesis that resveratrol promotes angiogenesis in cerebral endothelial cells and dissected the signaling pathways involved. Treatment of cerebral endothelial cells with resveratrol promoted proliferation, migration, and tube formation in Matrigel assays. Consistent with these pro-angiogenic responses, resveratrol altered endothelial morphology resulting in cytoskeletal rearrangements of β-catenin and VE-cadherin. These effects of resveratrol were accompanied by activation of phosphoinositide 3 kinase (PI3-K)/Akt and Mitogen-Activated Protein Kinase (MAPK)/ERK signaling pathways that led to endothelial nitric oxide synthase upregulation and increased nitric oxide (NO) levels. Subsequently, elevated NO signaling increased vascular endothelial growth factor and matrix metalloproteinase levels. Sequential blockade of these signaling steps prevented resveratrol-induced angiogenesis in cerebral endothelial cells. These findings provide a mechanistic basis for the potential use of resveratrol as a candidate therapy to promote angiogenesis and neurovascular recovery after stroke.

scholarly journals A 60% Edible Ethanolic Extract of Ulmus davidiana Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 781
Author(s):  
Jeongho Park ◽  
Hyun-Ouk Kim ◽  
Kwang-Hyun Park ◽  
Myung-Bok Wie ◽  
Sun-Eun Choi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Ethanolic Extract ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Ulmus Davidiana ◽  
And Migration ◽  
Endothelial Growth Factor

As abnormal angiogenesis is associated with exacerbation of various diseases, precise control over angiogenesis is imperative. Vascular endothelial growth factor (VEGF), the most well-known angiogenic factor, binds to VEGF receptor (VEGFR), activates various signaling pathways, and mediates angiogenesis. Therefore, blocking the VEGF-induced angiogenic response-related signaling pathways may alleviate various disease symptoms through inhibition of angiogenesis. Ulmus davidiana is a safe natural product that has been traditionally consumed, but its effects on endothelial cells (ECs) and the underlying mechanism of action are unclear. In the present study, we focused on the effect of a 60% edible ethanolic extract of U. davidiana (U60E) on angiogenesis. U60E inhibited the VEGF-mediated proliferation, tube formation, and migration ability of ECs. Mechanistically, U60E inhibited endothelial nitric oxide synthase activation and nitric oxide production by blocking the protein kinase B signaling pathway activated by VEGF and consequently inhibiting proliferation, tube formation, and migration of ECs. These results suggest that U60E could be a potential and safe therapeutic agent capable of suppressing proangiogenic diseases by inhibiting VEGF-induced angiogenesis.

scholarly journals Vascular endothelial growth factor-A signaling in bone marrow-derived endothelial progenitor cells exposed to hypoxic stress

2013 ◽  
Vol 45 (21) ◽  
pp. 1021-1034 ◽  
Author(s):  
Brian R. Hoffmann ◽  
Jordan R. Wagner ◽  
Anthony R. Prisco ◽  
Agnieszka Janiak ◽  
Andrew S. Greene
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Endothelial Progenitor ◽  
Endothelial Growth Factor

Bone marrow-derived endothelial progenitor cells (BM-EPCs) are stimulated by vascular endothelial growth factor-A (VEGF-A) and other potent proangiogenic factors. During angiogenesis, an increase in VEGF-A expression stimulates BM-EPCs to enhance endothelial tube formation and contribute to an increase in microvessel density. Hypoxia is known to produce an enhanced angiogenic response and heightened levels of VEGF-A have been seen in oxygen deprived epithelial and endothelial cells, yet the pathways for VEGF-A signaling in BM-EPCs have not been described. This study explores the influence of hypoxia on VEGF-A signaling in rat BM-EPCs utilizing a novel proteomic strategy to directly identify interacting downstream components of the combined VEGF receptor(s) signaling pathways, gene expression analysis, and functional phenotyping. VEGF-A signaling network analysis following liquid chromatographic separation and tandem mass spectrometry revealed proteins related to inositol/calcium signaling, nitric oxide signaling, cell survival, cell migration, and inflammatory responses. Alterations in BM-EPC expression of common angiogenic genes and tube formation in response to VEGF-A during hypoxia were measured and combined with the proteomic analysis to enhance and support the signaling pathways detected. BM-EPC tube formation assays in response to VEGF-A exhibited little tube formation; however, a cell projection/migratory phenotype supported the signaling data. Additionally, a novel assay measuring BM-EPC incorporation into preformed endothelial cell tubes indicated a significant increase of incorporated BM-EPCs after pretreatment with VEGF-A during hypoxia. This study verifies known VEGF-A pathway components and reveals several unidentified mechanisms of VEGF-A signaling in BM-EPCs during hypoxia that may be important for migration to sites of vascular regeneration.

Variable effects of alpha v suppression on VEGFR-2 expression in endothelial cells of different vascular beds

2009 ◽  
Vol 102 (11) ◽  
pp. 975-982 ◽  
Author(s):  
Tami Livnat ◽  
Uri Seligsohn ◽  
Rima Dardik
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Tube Formation ◽  
Vascular Endothelial ◽  
Mobility Shift ◽  
Genetic Ablation ◽  
Vascular Beds ◽  
Endothelial Growth Factor

SummaryIntegrins αvβ3 and αvβ5 have been long considered as proangiogenic receptors, yet genetic ablation studies demonstrated enhanced angiogenesis in mice lacking αvβ3 and αvβ5 integrins, which was attributed to increased expression of vascular endothelial growth factor receptor-2 (VEGFR-2). In this study, we determined the effect of αvβ3 and αvβ5 suppression in endothelial cells (EC) on vascular endothelial growth factor (VEGF) and VEGFR-2 expression. αv was suppressed by shRNA in HUVEC (venous endothelial cells) and HMVEC (microvascular endothelial cells).VEGFR-2 was significantly upregulated by αv suppression in HUVEC and downregulated in HMVEC at both mRNA and protein levels,as assessed by real-time PCR and flow cytometry,respectively.HMVEC displayed completely abolished Sp1 binding to the VEGFR-2 promoter, and HUVEC exhibited enhanced binding to the –170 E- Box element in the VEGFR-2 promoter, assessed by electrophoretic mobility shift assay. Realtime PCR also revealed opposite effects on the expression of 5 additional important genes involved in angiogenesis in the two cell types.VEGF mRNA expression was enhanced in HUVEC and reduced in HMVEC; however, these alterations were not statistically significant.VEGF-induced proliferation was upregulated in HUVEC and reduced in HMVEC following αv suppression. No tube formation on Matrigel was observed in αv suppressed cells, regardless of their origin.These results indicate that suppression of αv integrins can either augment or inhibit VEGFR-2 levels and VEGF-induced proliferation in EC from different vascular beds. Hence, therapeutic antiangiogenic intervention by siRN-Amediated suppression of αv integrins should take into account variable and potentially hazardous responses in different vascular beds.

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