Notoginsenoside Ft1 promotes angiogenesis via HIF-1α mediated VEGF secretion and the regulation of PI3K/AKT and Raf/MEK/ERK signaling pathways

Kaikai, Shen; Ji, Lili; Gong, Chenyuan; Ma, Yibo; Yang, Li; Fan, Yi; Hou, Maoqi; Wang, Zhengtao

doi:10.1016/j.bcp.2012.05.024

Cited by 74 publications

(49 citation statements)

References 36 publications

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“…The formation of new blood vessels is essential to nourish the newly formed granulation tissue and the survival of keratinocytes. Our previous study showed that Ft1 induces proliferation, migration, and tube formation of cultured human umbilical vein endothelial cells (Shen et al, 2012), which are used extensively as an in vitro model for angiogenesis research (Park et al, 2006). The proliferation, migration, and formation of tubular structure of endothelial cells are the indications for the development of new blood vessels from pre-existing vascular bed in angiogenesis (Holash et al, 1999;Lamalice et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…1), a saponin molecule, was first isolated from the leaves of P. notoginseng in 2006 (Chen et al, 2006). Our group previously reported that Ft1 was useful not only as a P 2 Y 12 agonist in enhancing platelet aggregation (Gao et al, 2014) but also as a stimulator of proliferation, migration, and tube formation in cultured human umbilical vein endothelial cells (Shen et al, 2012). These two properties indicated its possible curative effect on wound healing.…”

Section: Introductionmentioning

confidence: 99%

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Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice

Zhang

Gao

Yang

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Wound healing requires the essential participation of fibroblasts, which is impaired in diabetic foot ulcers (DFU). Notoginsenoside Ft1 (Ft1), a saponin from Panax notoginseng, can enhance platelet aggregation by activating signaling network mediated through P 2 Y 12 and induce proliferation, migration, and tube formation in cultured human umbilical vein endothelial cells. However, whether it can accelerate fibroblast proliferation and benefit wound healing, especially DFU, has not been elucidated. In the present study on human dermal fibroblast HDF-a, Ft1 increased cell proliferation and collagen production via PI3K/Akt/ mTOR signaling pathway. On the excisional wound splinting model established on db/db diabetic mouse, topical application of Ft1 significantly shortened the wound closure time by 5.1 days in contrast with phosphate-buffered saline (PBS) treatment (15.8 versus 20.9 days). Meanwhile, Ft1 increased the rate of reepithelialization and the amount of granulation tissue at day 7 and day 14. The molecule also enhanced mRNA expressions of COL1A1, COL3A1, transforming growth factor (TGF)-b1 and TGF-b3 and fibronectin, the genes that contributed to collagen expression, fibroblast proliferation, and consequent scar formation. Moreover, Ft1 facilitated the neovascularization accompanied with elevated vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor at either mRNA or protein levels and alleviated the inflammation of infiltrated monocytes indicated by reduced tumor necrosis factor-a and interleukin-6 mRNA expressions in the diabetic wounds. Altogether, these results indicated that Ft1 might accelerate diabetic wound healing by orchestrating multiple processes, including promoting fibroblast proliferation, enhancing angiogenesis, and attenuating inflammatory response, which provided a great potential application of it in clinics for patients with DFU.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice

Zhang

Gao

Yang

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Indeed, ERK signaling is one of the major pathways that is responsible for VEGF expression induced by various stimuli in transformed or nontransformed cells (29,30). Of note, activation of ERK signaling seems to increase translocation of hypoxia-inducible factor 1a (HIF-1a) from cytoplasm to nuclei, consequently it binds to the VEGF promoter and initiates the transcription of the growth factor (31). Considering elevated contents of HIF1a are a universal feature in tumor cells, including colon carcinoma cells (22), it is plausible that GM-CSF-elicited VEGF expression in CEC in chronic inflammatory microenvironment is attributed to, at least in part, increased HIF-1a translocation.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF

et al. 2014

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“…Both cascades are required for angiogenic sprout formation and for survival of EC in the newly formed vessel (46), and both cascades are inhibited by VEGFR-2 antagonists (26, 60). However, we observed that ERK1/2 phosphorylation was essentially unaffected by TIMAP depletion, whereas phosphorylation of Akt on S473 and T308 was profoundly reduced by TIMAP silencing in EC grown in serum-replete medium.…”

Section: Discussionmentioning

confidence: 99%

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

Obeidat

Ballermann

2014

American Journal of Physiology-Renal Physiology

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Obeidat M, Li L, Ballermann BJ. TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells. Am J Physiol Renal Physiol 307: F623-F633, 2014. First published July 9, 2014 doi:10.1152/ajprenal.00070.2014.-The function of TIMAP, an endothelial cell (EC)-predominant protein phosphatase 1-regulatory subunit, is poorly understood. We explored the potential role of TIMAP in the Akt-dependent regulation of glomerular EC proliferation, survival, and in vitro angiogenesis. To deplete TIMAP, the EC were transfected with TIMAP-specific or nonspecific small interfering (si) RNA. The rate of electrical impedance development across subconfluent EC monolayers, a measure of the time-dependent increase in EC number, was 93 Ϯ 2% lower in TIMAP-depleted than in control EC. This effect on cell proliferation was associated with reduced DNA synthesis and increased apoptosis: TIMAP silencing reduced 5-ethynyl-2=-deoxyuridine incorporation by 38 Ϯ 2% during the exponential phase of EC proliferation, and cleaved caspase 3 as well as caspase 3 activity increased in TIMAPdepleted relative to control cells. Furthermore, TIMAP depletion inhibited the formation of angiogenic sprouts by glomerular EC in three-dimensional culture. TIMAP depletion strongly diminished growth factor-stimulated Akt phosphorylation without altering ERK1/2 phosphorylation, suggesting a specific effect on the PI3K/ Akt/PTEN pathway. Endogenous TIMAP and PTEN colocalized in EC and coimmunoprecipitated from EC lysates. The inhibitory PTEN phosphorylation on S370 was significantly reduced in TIMAP-depleted compared with control EC, while phosphorylation of PTEN on the S380/T382/T383 cluster remained unchanged. Finally, the PTEN inhibitor bpV(phen) fully reversed the suppressive effect of TIMAP depletion on Akt phosphorylation. The data indicate that in growing EC, TIMAP is necessary for Akt-dependent EC proliferation, survival, and angiogenic sprout formation and that this effect of TIMAP is mediated by inhibition of the tumor suppressor PTEN. endothelial cells; PTEN; protein phosphatase 1-regulatory subunit; PPP1R16B; apoptosis; clectric cell-substrate impedance sensing MECHANISMS THAT REGULATE ANGIOGENESIS have received massive attention since Folkman (15) first advanced the theory that tumor growth depends on new blood vessel formation. Angiogenesis involves the sprouting and elongation of new blood vessels from preexisting vessels followed by stabilization and vessel specification (28). This process is crucial for normal blood vessel formation and patterning during embryonic development, for postembryonic blood vessel repair (5), and remodeling in response to hypoxia, in the female reproductive cycle, and for the establishment of the placental vasculature. Pathological retinal and tumor vascularization also depend on angiogenesis. While endothelial cells (EC) at the tip of the angiogenic sprout determine the direction and pattern of new blood vessel growth, elongation of the new vessel stalk requires EC proliferatio...

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Notoginsenoside Ft1 promotes angiogenesis via HIF-1α mediated VEGF secretion and the regulation of PI3K/AKT and Raf/MEK/ERK signaling pathways

Cited by 74 publications

References 36 publications

Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice

Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice

Tumor-Derived GM-CSF Promotes Inflammatory Colon Carcinogenesis via Stimulating Epithelial Release of VEGF

TIMAP promotes angiogenesis by suppressing PTEN-mediated Akt inhibition in human glomerular endothelial cells

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