Pentoxifylline inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures

Niderla-Bielińska, Justyna; Bartkowiak, Krzysztof; Ciszek, Bogdan; Czajkowski, Eric; Jankowska‐Steifer, Ewa; Krejner, Alicja; Ratajska, Anna

doi:10.1016/j.ejphar.2018.03.015

Cited by 12 publications

(13 citation statements)

References 33 publications

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“…It has been shown that caffeine inhibits growth factors involved in angiogenesis in different cellular models [ 16 , 17 , 20 ]. In addition, evidence is available showing that other methylxanthines, such as pentoxifylline [ 27 ] and theophylline [ 28 ], possess antiangiogenic properties. Pharmacological studies with adenosine receptor agonists and antagonists may help in elucidating the functional target(s) of caffeine responsible for its capacity to inhibit angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

Basnet

Zizioli

Muscò

et al. 2021

IJMS

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In this study, we report the effects of caffeine on angiogenesis in zebrafish embryos both during normal development and after exposure to Fibroblast Growth Factor 2 (FGF2). As markers of angiogenesis, we measured the length and width of intersegmental vessels (ISVs), performed whole-mount in situ hybridization with fli1 and cadh5 vascular markers, and counted the number of interconnecting vessels (ICVs) in sub-intestinal venous plexus (SIVP). In addition, we measured angiogenesis after performing zebrafish yolk membrane (ZFYM) assay with microinjection of fibroblast growth factor 2 (FGF2) and perivitelline tumor xenograft assay with microinjection of tumorigenic FGF2-overexpressing endothelial (FGF2-T-MAE) cells. The results showed that caffeine treatment causes a shortening and thinning of ISVs along with a decreased expression of the vascular marker genes and a decrease in the number of ICVs in the SIVP. Caffeine was also able to block angiogenesis induced by exogenous FGF2 or FGF2-producing cells. Overall, our results are suggestive of the inhibitory effect of caffeine in both direct and indirect angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

Basnet

Zizioli

Muscò

et al. 2021

IJMS

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“…It induces vascular dilation and increases erythrocyte flexibility resulting in enhanced blood flow . PTX indirectly inhibits angiogenesis in mouse pro‐epicardial explant cultures but has no significant effect on the C166 endothelial cell line . It also has anti‐tumour necrosis factor α activity and is believed to reduce the cytokine cascade.…”

Section: Discussionmentioning

confidence: 99%

The Akt/FoxO/p27^Kip1 axis contributes to the anti‐proliferation of pentoxifylline in hypertrophic scars

Yang

Chen

Yang

et al. 2019

J Cellular Molecular Medi

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Hypertrophic scars (HS) are characterized by the excessive production and deposition of extracellular matrix (ECM) proteins. Pentoxifylline (PTX), a xanthine derived antioxidant, inhibits the proliferation, inflammation and ECM accumulation of HS. In this study, we aimed to explore the effect of PTX on HS and further clarify the mechanism of PTX‐induced anti‐proliferation. We found that PTX could significantly attenuate proliferation of HS fibroblasts and fibrosis in an animal HS model. PTX inhibited the proliferation of HSFs in a dose‐ and time‐dependent manner, and this growth inhibition was mainly mediated by cell cycle arrest. Transcriptome sequencing showed that PTX affects HS formation through the PI3K/Akt/FoxO1 signalling pathway to activate p27Kip1. PTX down‐regulated p‐Akt and up‐regulated p‐FoxO1 in TGF‐β1 stimulated fibroblasts at the protein level, and simultaneously, the expression of p27Kip1 was activated. In a mouse model of HS, PTX treatment resulted in the ordering of collagen fibres. The results revealed that PTX regulates TGFβ1‐induced fibroblast activation and inhibits excessive scar formation. Therefore, PTX is a promising agent for the treatment of HS formation.

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“…This was further confirmed with transmission electron microscopic studies, which showed the endothelium of proepicardial vessels to be covered by a discontinuous basement membrane; it also showed that cytoplasmic vesicles, which are typical for a mature and metabolically active endothelium, were scarce (Niderla‐Bielinska et al, ). PE explants, isolated from mice and cultured on collagen or Matrigel under the influence of angiogenic factors (VEGF, bFGF) can give rise to vascular sprouts, which are continuous with proepicardial explant vessels (Niderla‐Bielinska et al, , ). Avian PE explants are also capable of forming vascular sprouts, both spontaneously and under the influence of proangiogenic factors (VEGF, bFGF) (Guadix et al, ).…”

Section: Introductionmentioning

confidence: 99%

Proepicardium: Current Understanding of its Structure, Induction, and Fate

Niderla-Bielińska

Jankowska‐Steifer

Flaht-Zabost

et al. 2018

The Anatomical Record

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The proepicardium (PE) is a transitory extracardiac embryonic structure which plays a crucial role in cardiac morphogenesis and delivers various cell lineages to the developing heart. The PE arises from the lateral plate mesoderm (LPM) and is present in all vertebrate species. During development, mesothelial cells of the PE reach the naked myocardium either as free‐floating aggregates in the form of vesicles or via a tissue bridge; subsequently, they attach to the myocardium and, finally, form the third layer of a mature heart—the epicardium. After undergoing epithelial‐to‐mesenchymal transition (EMT) some of the epicardial cells migrate into the myocardial wall and differentiate into fibroblasts, smooth muscle cells, and possibly other cell types. Despite many recent findings, the molecular pathways that control not only proepicardial induction and differentiation but also epicardial formation and epicardial cell fate are poorly understood. Knowledge about these events is essential because molecular mechanisms that occur during embryonic development have been shown to be reactivated in pathological conditions, for example, after myocardial infarction, during hypertensive heart disease or other cardiovascular diseases. Therefore, in this review we intended to summarize the current knowledge about PE formation and structure, as well as proepicardial cell fate in animals commonly used as models for studies on heart development. Anat Rec, 302:893–903, 2019. © 2018 Wiley Periodicals, Inc.

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Pentoxifylline inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures

Cited by 12 publications

References 33 publications

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

The Akt/FoxO/p27^Kip1 axis contributes to the anti‐proliferation of pentoxifylline in hypertrophic scars

Proepicardium: Current Understanding of its Structure, Induction, and Fate

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Pentoxifylline inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures

Cited by 12 publications

References 33 publications

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

Caffeine Inhibits Direct and Indirect Angiogenesis in Zebrafish Embryos

The Akt/FoxO/p27Kip1 axis contributes to the anti‐proliferation of pentoxifylline in hypertrophic scars

Proepicardium: Current Understanding of its Structure, Induction, and Fate

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The Akt/FoxO/p27^Kip1 axis contributes to the anti‐proliferation of pentoxifylline in hypertrophic scars