Role of PI3K/Akt and MEK/ERK in Mediating Hypoxia-Induced Expression of HIF-1α and VEGF in Laser-Induced Rat Choroidal Neovascularization

Xiao-sheng, Yang; Wang, Yusheng; Zhang, Jian; Li, Yan; Xu, Jianfeng; Zhu, Jie; Zhao, Wei; Chu, Dake; Wiedemann, Peter

doi:10.1167/iovs.08-2591

Cited by 141 publications

(119 citation statements)

References 33 publications

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“…VEGF is one of the most well-characterized angiogenic factors in CNV and is regulated by HIF-1 (17). Previous studies have demonstrated that hypoxia induces VEGF production in several cell types (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of dickkopf2 inhibits vascular endothelia growth factor expression through the Wnt/β-catenin signaling pathway in human retinal pigment epithelial cells under hypoxic conditions

Zhao

Liu

et al. 2018

Exp Ther Med

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Abstract. Hypoxia has been demonstrated to be a proangiogenic factor that induces vascular endothelial growth factor (VEGF) in retinal pigment epithelial (RPE) cells. Dickkopf2 (DKK2), originally known as Wnt antagonist, has recently been demonstrated to have an important regulatory role in angiogenesis; however, the specific role of DKK2 in RPE cells is not known. In the present study, the effects of DKK2 on VEGF expression under hypoxic conditions were investigated, as well as the molecular mechanisms involved. The results demonstrated that the expression of DKK2 was markedly increased under hypoxic conditions compared with normoxic conditions. Knockdown of DKK2 markedly attenuated the CoCl 2 -induced expression of hypoxia-inducible factor (HIF)-1α and VEGF in RPE cells. Furthermore, knockdown of DKK2 markedly inhibited the expression of β-catenin induced by hypoxia. In conclusion, the findings of the present study demonstrate that knockdown of DKK2 inhibits the hypoxia-induced production of VEGF by suppressing the activation of the Wnt/β-catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Knockdown of dickkopf2 inhibits vascular endothelia growth factor expression through the Wnt/β-catenin signaling pathway in human retinal pigment epithelial cells under hypoxic conditions

Zhao

Liu

et al. 2018

Exp Ther Med

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“…The PI3K/Akt pathway is activated during ischemia and angiogenesis (Yang et al, 2009). It regulates a variety of cellular processes and plays a critical role in controlling the balance between cell survival and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV Stimulates Angiogenesis and Increases Hypoxia-Inducible Factor-1α Accumulation via Phosphatidylinositol 3-Kinase/Akt Pathway

Zhang

Liu²,

Lu³

et al. 2011

J Pharmacol Exp Ther

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Astragaloside IV is the major active constituent of Astragalus membranaceus, which has been widely used for the treatment of cardiovascular diseases in China. The aim of this study was to determine the angiogenic effect of astragaloside IV and its underlying mechanism. We used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, Western blotting, real-time polymerase chain reaction, and immunofluorescence to detect the effect of astragaloside IV on proliferation of human umbilical vein endothelial cells (HUVECs), the phospho-Akt protein level, hypoxia-inducible factor-1␣ (HIF-1␣) accumulation, vascular endothelial growth factor mRNA expression, and applied cell migration, tube formation, and chick chorioallantoic membrane assays to study the angiogenic effect of astragaloside IV. Results indicate that astragaloside IV promoted cell proliferation and stimulated HIF-1␣ accumulation during hypoxia. Mechanism studies revealed that astragaloside IV did not affect the degradation of HIF-1␣ protein or the level of HIF-1␣ mRNA. In contrast, astragaloside IV apparently activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates HIF-1␣ protein synthesis. Moreover, astragaloside IV also stimulated cell migration, increased tube formation, and promoted angiogenesis in the chick chorioallantoic membrane assay. All angiogenic effects of astragaloside IV were reversed by the PI3K inhibitor. Taken together, our data collectively reveal that astragaloside IV is a novel regulator of HIF-1␣ and angiogenesis through the PI3K/Akt pathway in HUVECs that are exposed to hypoxia.

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“…Thus, hypoxia may have a central role in the development of submacular wound healing, which in turn leads to the production of HIF-1, itself the key trigger for VEGF production and the subsequent development of the neovascular component of this submacular tissue repair. 52 HIF-1 regulates many angiogenic factors such as VEGF, VEGFR-1, erythropoietin, inductible nitric oxide synthase, endothelin-1 and plateletderived growth factor-B, which have important and diverse roles in different stages of angiogenesis. 28,53 Earlier studies have indicated that disruption of the binding between HIF-1 and proangiogenic promoters may selectively diminish the activation of the HIF-1-driven target genes.…”

Section: Discussionmentioning

confidence: 99%

“…As notable expression of HIF-1a was detectable since 1 day after laser photocoagulation and peaked at 3 day in pervious research, 52 the specimens at 3 day after laser photocoagulation were chosen for semiquantitative analysis of HIF-1a protein expression. Cryostat sections were dried in the air and rehydrated with PBS, blocked for 2 h in PBS containing 5% bovine serum albumin, 5% normal goat serum, and 1% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

Zhang

et al. 2009

Gene Ther

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The aim of this study was to evaluate the possibility of poly (D, L-lactide-co-glycolide) nanoparticle (NPs) as a gene vector for functional plasmid DNA (pDNA) and to investigate its inhibitory efficacy on experimental choroidal neovascularization (CNV). We developed intravitreal administered, hypoxia-inducible factor 1a (HIF-1a) short hairpin RNA and green fluorescent protein (GFP) co-expressed pDNA-loaded NPs (pshHIF-1a NPs). CNV was induced by laser photocoagulation in 112 rats. The rats were then randomly assigned to be injected intravitreally with phosphate-buffered saline (PBS), blank NPs, naked pDNA, control pDNA NPs and pshHIF-1a NPs, respectively, and non-injection group was set as the control. Immunofluorescence staining, fluorescein fundus angiography and histologic analysis were performed to evaluate the inhibitory efficacy on CNV. The results showed that the expression of GFP preferentially localized in the retinal pigment epithelium cell layer and lasted for 4 weeks. The fluorescein leakage areas of CNV were significantly larger in the PBS, blank NPs, control pDNA NPs, non-injection group and naked pDNA group than in pshHIF-1a NPs group (Po0.01). The mean thickness of the CNV lesions in the intravitreally pshHIF1a NPs-treated group was significantly smaller than other groups (Po0.01). No signs of functional or ultrastructural destruction in retina were detected. Therefore, pshHIF-1a NPs may act as a novel therapeutic option to transfer specific pDNA and inhibit the formation of experimental CNV.

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Role of PI3K/Akt and MEK/ERK in Mediating Hypoxia-Induced Expression of HIF-1α and VEGF in Laser-Induced Rat Choroidal Neovascularization

Abstract: The PI3K/Akt pathway was required for hypoxia-induced expression of HIF-1alpha and VEGF, whereas the MEK/ERK pathway was required only for VEGF in laser-induced rat CNV.

Cited by 141 publications

References 33 publications

Knockdown of dickkopf2 inhibits vascular endothelia growth factor expression through the Wnt/β-catenin signaling pathway in human retinal pigment epithelial cells under hypoxic conditions

Knockdown of dickkopf2 inhibits vascular endothelia growth factor expression through the Wnt/β-catenin signaling pathway in human retinal pigment epithelial cells under hypoxic conditions

Astragaloside IV Stimulates Angiogenesis and Increases Hypoxia-Inducible Factor-1α Accumulation via Phosphatidylinositol 3-Kinase/Akt Pathway

Inhibitory efficacy of hypoxia-inducible factor 1α short hairpin RNA plasmid DNA-loaded poly (D, L-lactide-co-glycolide) nanoparticles on choroidal neovascularization in a laser-induced rat model

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