KLF4 Promotes Angiogenesis by Activating VEGF Signaling in Human Retinal Microvascular Endothelial Cells

Wang, Yinan; Yang, Chuanhe; Gu, Qun; Sims, Michelle; Gu, Wei; Pfeffer, Lawrence M.; Yue, Junming

doi:10.1371/journal.pone.0130341

Cited by 46 publications

(44 citation statements)

References 37 publications

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“…It has been shown that inhibition of KLF4 results in an increase of NF-kB transcriptional activity and the expression of downstream prothrombotic, proinflammatory genes (76). KLF4 is a positive regulator of proliferation, migration, and tube formation in human retinal microvascular endothelial cells via upregulation of vascular endothelial growth factor (VEGF) levels (77). …”

Section: Physiological Functions In Tissues and Organsmentioning

confidence: 99%

Krüppel-like factor 4 (KLF4): What we currently know

Ghaleb

Yang

2017

Gene

419

349

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Krüppel-like factor 4 (KLF4) is an evolutionarily conserved zinc finger-containing transcription factor that regulates diverse cellular processes such as cell growth, proliferation, and differentiation. Since its discovery in 1996, KLF4 has been gaining a lot of attention, after it was shown in 2006 as one of four factors required for the induction of pluripotent stem cells (iPSCs). Here we review the current knowledge on the different functions and roles of KLF4 in various tissue and organ systems.

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Section: Physiological Functions In Tissues and Organsmentioning

confidence: 99%

Krüppel-like factor 4 (KLF4): What we currently know

Ghaleb

Yang

2017

Gene

419

349

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“…89 Interestingly, these two transcription factors appear to have discrepant effects on VEGFA-VEGFR2 signaling: KLF2 overexpression in human umbilical vein cells inhibited VEGFR2 mRNA and protein expression, as well as promoter activity, suggesting an antiangiogenic effect, 90 whereas KLF4 has been demonstrated to positively regulate VEGFA expression. 91 Further exploration of these signaling pathways is warranted to elucidate the mechanisms by which VEGF inhibition contributes to the nephrotoxicity observed in clinical practice.…”

Section: Enos Signalingmentioning

confidence: 99%

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

Estrada

Maldonado

Mallipattu

2019

JASN

142

153

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Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in oncology, with new drugs continuously in development. In this review, we consider the experimental and clinical evidence behind the diverse nephrotoxicities associated with the inhibition of this pathway. We also review the renal effects of VEGF inhibition's mediation of key downstream signaling pathways, specifically MAPK/ ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Reports also indicate that tyrosine kinase inhibition of the VEGF receptors is preferentially associated with glomerulopathies such as minimal change disease and FSGS. Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with albuminuria and podocyte injury, but has also been linked to renal-specific TMA. In all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 inhibitors contribute to nephrotoxicity, as well as the wide range of clinical manifestations that have been reported with their use. We also highlight potential avenues for future research to elucidate mechanisms for minimizing nephrotoxicity while maintaining therapeutic efficacy.

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“…* P < 0.05 versus control. airway angiogenesis (Ghelfi et al 2013;Wang et al 2015). We investigated the potential role of VEGF signalling in the regulation of the pro-angiogenic ability of the ASM cells by STAT3 in vitro.…”

Section: Inhibition Of Stat3 Activation In Asm Cells Decreases the mentioning

confidence: 99%

STAT3 potentiates the ability of airway smooth muscle cells to promote angiogenesis by regulating VEGF signalling

Sun

Mai

et al. 2017

Experimental Physiology

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What is the central question of this study? Airway angiogenesis occurs in asthma, and airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis. What is the potential mechanism by which ASM cells harvested from patients with asthma are capable of promoting airway angiogenesis? What is the main finding and its importance? Endogenous STAT3 mediated the pro-angiogenic ability of ASM cells by directly activating VEGF signalling. These findings contribute to the understanding of airway angiogenesis in pathology and could represent a possible therapeutic target for asthma. Airway angiogenesis indicates the specific vascular structure remodelling that occurs in asthma. Airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis; however, the potential mechanism is not yet fully defined. Herein, we investigated the role of signal transducer and activator of transcription 3 (STAT3) in the progress of airway angiogenesis. Western blot analysis showed that STAT3 activation was aberrantly upregulated in ASM tissues of patients with asthma and ASM cells that were exposed to cytokines to imitate the airway conditions in patients with asthma. Compared with the control group, both the inhibition of STAT3 activation and the silencing of endogenous STAT3 in ASM cells significantly reduced the proliferation, migration and tube-forming ability of human lung microvascular endothelial cells induced by the conditioned medium (CM) of ASM cells. The increased proliferation and migration of human aortic vascular smooth muscle cells were also repressed by inhibition of STAT3 in ASM cells. Besides, the increased activity of VEGF signalling was observed in ASM cells and the CM by RT-PCR and Western blotting assay, whereas this increased activity was reduced by STAT3 silencing. Further studies indicated that STAT3 regulated VEGF activation by directly interacting with the binding site on the 5' region of the VEGF gene. The increase in STAT3-induced pro-angiogenic activity of ASM cells was significantly decreased by administration of VEGF neutralizing antibody. In conclusion, we provided evidence that endogenous STAT3 mediates the pro-angiogenic ability of ASM cells by directly activating VEGF signalling, which could represent a possible therapeutic target for asthma.

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KLF4 Promotes Angiogenesis by Activating VEGF Signaling in Human Retinal Microvascular Endothelial Cells

Cited by 46 publications

References 37 publications

Krüppel-like factor 4 (KLF4): What we currently know

Krüppel-like factor 4 (KLF4): What we currently know

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

STAT3 potentiates the ability of airway smooth muscle cells to promote angiogenesis by regulating VEGF signalling

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