FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds

Jeon, Hyeran Helen; Yu, Quan; Lu, Yang; Spencer, Evelyn; Lu, Chanyi; Milovanova, Tatyana N.; Yang, Yang; Zhang, Chenying; Stepanchenko, Olga; Vafa, Rameen P.; Coelho, Paulo G.; Graves, Dana T.

doi:10.1002/path.5075

Cited by 63 publications

(52 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To explain this discrepancy, FOXO1 may be a factor. FOXO1 directly regulated VEGF‐A expression during wound healing and its regulation and downstream targets were affected by AGEs. FOXO1 expression can positively or negatively modulate cell behaviors by its differential effects on downstream targets and more importantly, its activity differs because the microenvironment alters the pattern of genes induced by FOXO1 .…”

Section: Discussionmentioning

confidence: 99%

Synergistic alveolar bone resorption by diabetic advanced glycation end products and mechanical forces

Moon

Lee

Kim

et al. 2019

Journal of Periodontology

View full text Add to dashboard Cite

Background The association between diabetes mellitus (DM) and bone diseases is acknowledged. However, the mechanistic pathways leading to the alveolar bone (AB) destruction remain unclear. This study aims to elucidate the mechanical forces (MF)‐induced AB destruction in DM and its underlying mechanism. Methods In vivo periodontal tissue responses to MF were evaluated in rats with diabetes. In vitro human periodontal ligament (PDL) cells were either treated with advanced glycation end products (AGEs) alone or with AGEs and MF. Results In vivo, the transcription of VEGF‐A, colony stimulating factor‐1 (CSF‐1), and Ager was upregulated in diabetes, whereas changes in DDOST and Glo1 mRNAs were negligible. DM induced VEGF‐A protein in the vascular cells of the PDL and subsequent angiogenesis, but DM itself did not induce osteoclastogenesis. MF‐induced AB resorption was augmented in DM, and such augmentation was morphologically substantiated by the occasional undermining resorption as well as the frontal resorption of the AB by osteoclasts. The mRNA levels of CSF‐1 and vascular endothelial growth factor (VEGF) during MF application were highly elevated in diabetes, compared with those of the normal counterparts. In vitro, AGEs treatment elevated Glut‐1 and CSF‐1 mRNA levels via the p38 and JNK pathways, whereas OGT and VEGF levels remained unchanged. Compressive MF especially caused upregulation of VEGF, CSF‐1, and Glut‐1 levels, and such upregulation was further enhanced by AGEs treatment. Conclusions Overloaded MF and AGEs metabolites may synergistically aggravate AB destruction by upregulating CSF‐1 and VEGF. Therefore, regulating the compressive overloading of teeth, as well as the levels of diabetic AGEs, may prove to be an effective therapeutic modality for managing DM‐induced AB destruction.

show abstract

Section: Discussionmentioning

confidence: 99%

Synergistic alveolar bone resorption by diabetic advanced glycation end products and mechanical forces

Moon

Lee

Kim

et al. 2019

Journal of Periodontology

View full text Add to dashboard Cite

show abstract

“…Reactive oxygen species (ROS) arising from inflammatory cells are strongly participated in the pathogenesis of chronic ulcers . ROS activates cellular molecular signals to disturb angiogenesis or cytokine secretion to delay wound healing . That is to say, excessive oxidative stress and impaired angiogenesis may delay wound healing.…”

Section: Introductionmentioning

confidence: 99%

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Hua

et al. 2019

Experimental Dermatology

View full text Add to dashboard Cite

Hydrogen sulphide (H2S) is an important gasotransmitter with several physiological functions. However, the roles and the detailed mechanisms of H2S on skin wound healing are not known well. In the present study, 129S1/SvImJ mice were intraperitoneally injected with NaHS (50 μmol/kg/d) for 2 weeks. Then, a round wound of 6 mm diameter with depth into the dermis was made. The skin wound area, blood perfusion, superoxide production, malondialdehyde (MDA) levels, total antioxidant capacity (T‐AOC), expression of vascular endothelial growth factor (VEGF), dynamin‐related protein 1 (DRP1) and optic atrophy 1 (OPA1) were measured. After NaHS (50 μmol/L) pre‐administration for 4 hours, cell migration rate, DRP1, OPA1 and α–smooth muscle actin (α‐SMA) expression, superoxide production and mitochondrial membrane potential in primary skin fibroblasts were measured. Tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in human keratinocytes were also measured. The results showed that NaHS pretreatment significantly accelerated wound healing and improved blood flow in the wound after operation. NaHS increased VEGF expression in the wound and promoted tube formation in HUVECs. Meanwhile, NaHS attenuated reactive oxygen species (ROS) production, suppressed MDA level but restored T‐AOC in the wound. NaHS also promoted skin fibroblasts migration and α‐SMA expression after scratch. Moreover, NaHS alleviated ROS, increased mitochondrial membrane potential, decreased DRP1 but enhanced OPA1 expression in skin fibroblasts after scratch. NaHS also accelerated human keratinocytes migration after scratch. Taken together, exogenous H2S supplementary accelerated the skin wound healing, which might be related to oxidative stress inhibition and VEGF enhancement.

show abstract

“…VEGF is expressed in many cell types including epidermal keratinocytes during wound healing. In this issue of The Journal of Pathology , Jeon et al elegantly demonstrate that forkhead box O1 (FoxO1), a member of the forkhead transcription factor family, regulates VEGF expression and promotes angiogenesis in healing wounds . Using a wound healing animal model, in which FoxO1 is specifically deleted in keratinocytes, they show that vascular density is significantly decreased in wounds, along with a decrease in the proliferation of endothelial cells and poor wound healing.…”

mentioning

confidence: 99%

“…Using chromatin‐immunoprecipitation assays, they further show that FoxO1 may regulate VEGF expression via interaction with the gene locus. A caveat is that only one FoxO1 response element exists on the VEGF promoter and is situated approximately 800 bp upstream of the transcription start site . It thus remains an open question as to how FoxO1 precisely regulates VEGF transcription.…”

mentioning

confidence: 99%

“…Importantly, FoxO1 may regulate the formation of functional vascular networks via priming pro‐angiogenic VEGF signaling through downregulating anti‐angiogenic CD36 signaling in the presence of lysophosphatidic acid . By showing that FoxO1 promotes VEGF expression in keratinocytes, the studies from Jeon et al add an additional layer to FoxO1 regulation of angiogenesis, even though the precise mechanisms are not yet understood (Figure ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

FoxO1 transcriptional activities in VEGF expression and beyond: a key regulator in functional angiogenesis?

Ren

2018

The Journal of Pathology

View full text Add to dashboard Cite

FoxO1 has emerged as an important regulator of angiogenesis. Recent work published in this Journal shows that FoxO1 regulates VEGF expression in keratinocytes and is required for angiogenesis in wound healing. Since FoxO1 also regulates CD36 transcription, and endothelial cell differentiation and vascular maturation, this transcription factor may be essential for the formation of functional vascular networks via coupling the regulation of CD36 in vascular endothelial cells under physiological and pathological conditions. Although many outstanding questions remain to be answered, the mechanisms by which FoxO1 regulates VEGF in keratinocytes provide insight into the development of functional angiogenesis and further our understanding of vascular biology. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

show abstract

FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds

Cited by 63 publications

References 18 publications

Synergistic alveolar bone resorption by diabetic advanced glycation end products and mechanical forces

Synergistic alveolar bone resorption by diabetic advanced glycation end products and mechanical forces

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

FoxO1 transcriptional activities in VEGF expression and beyond: a key regulator in functional angiogenesis?

Contact Info

Product

Resources

About