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Ravinarayanan Haribalaganesh Sardarpasha Sheikpranbabu Banumathi Elayappan Deepak Venkataraman Sangiliyandi Gurunathan 《Angiogenesis》2009,12(4):381-389
Pigment epithelium–derived factor (PEDF) is a well-known protease inhibitor for angiogenesis in the eye, suggesting that loss
of PEDF in eye is implicated in the pathogenesis of proliferative diabetic retinopathy. Since the role of PEDF in diabetic
retinopathy is unclear, the effect of PEDF on different types of cells constituting the blood vessel has to be checked. Here,
we have investigated the effects of PEDF under hyperglycemic conditions in retinal pericytes, isolated from goat’s eye and
used to analyze the signaling pathway involved. High glucose increased the apoptotic cell death and intracellular reactive
oxygen species generation, which was blocked on the addition of PEDF. PEDF was found to inhibit the apoptotic cell death and
protect the cells via activating the PI3K/Akt pathway, which was analyzed with dominant negative Akt and constitutively active
Akt–transfected cells. These results demonstrate that PEDF protects pericytes against the high glucose–induced apoptosis and
dysfunction. 相似文献
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Kalishwaralal K Sheikpranbabu S BarathManiKanth S Haribalaganesh R Ramkumarpandian S Gurunathan S 《Angiogenesis》2011,14(1):29-45
The purpose of this study was to investigate the effect of gold nanoparticles on the signaling cascade related to angiogenesis
and vascular permeability induced by Vascular Endothelial Growth Factor (VEGF) in Bovine retinal endothelial cells (BRECs).
The effect of VEGF and gold nanoparticles on cell viability, migration and tubule formation was assessed. PP2 (Src Tyrosine
Kinase inhibitor) was used as the positive control and the inhibitor assay was performed to compare the effect of AuNPs on
VEGF induced angiogenesis. The transient transfection assay was performed to study the VEGFR2/Src activity during experimental
conditions and was confirmed using western blot analysis. Treatment of BRECs with VEGF significantly increased the cell proliferation,
migration and tube formation. Furthermore, gold nanoparticles (500 nM) significantly inhibited the proliferation, migration
and tube formation, in the presence of VEGF in BRECs. The gold nanoparticles also inhibited VEGF induced Src phosphorylation
through which their mode of action in inhibiting angiogenic pathways is revealed. The fate of the gold nanoparticles within
the cells is being analyzed using the TEM images obtained. The potential of AuNPs to inhibit the VEGF165-induced VEGFR-2 phosphorylation
is also being confirmed through the receptor assay which elucidates one of the possible mechanism by which AuNPs inhibit VEGF
induced angiogenesis. These results indicate that gold nanoparticles can block VEGF activation of important signaling pathways,
specifically Src in BRECs and hence modulation of these pathways may contribute to gold nanoparticles ability to block VEGF-induced
retinal neovascularization. 相似文献
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Banumathi Elayappan Haribalaganesh Ravinarayannan Sheik Pran Babu Sardar Pasha Kyung-jin Lee Sangiliyandi Gurunathan 《Angiogenesis》2009,12(4):313-324
Retinal angiogenesis in diabetes may lead to visual impairment and even irreversible blindness in people of working age group
worldwide. The main pathological feature of proliferative diabetic retinopathy (PDR) is hypoxia, and overproduction of growth
factors like vascular endothelial growth factor (VEGF) and erythropoietin (Epo). This results in pathological proliferation
of retinal endothelial cells (RECs), leading to new vessel formation (angiogenesis). Inhibition of angiogenesis is a promising
strategy for treatment of PDR and other retinal neovascular disorders. Pigment epithelium-derived factor (PEDF), a 50-kDa
protein secreted by retinal pigment epithelium, inhibits the growth of new blood vessel induced in the eye in a variety of
ways with a yet elusive mechanism. Here, we investigated the possible mechanism by which PEDF inhibits VEGF- and Epo-induced
angiogenic effects in RECs is mediated through PI3K/Akt pathway. PEDF treatment induced the apoptosis in RECs by activating
caspase-3 and DNA fragmentation. We found a dose-dependent increase in cell survival with VEGF or Epo, which was attenuated
in the presence of PEDF. In addition, PEDF significantly (P < 0.05) inhibited migration and in vitro tube formation in RECs in the presence of VEGF as like PI3K/Akt inhibitor. Of interest,
PEDF effectively abrogated VEGF-mediated phosphorylation of PI3K/Akt. Further studies using RECs transfected with constitutively
active and dominant-negative forms of Akt suggest that PEDF could inhibit VEGF- and also Epo-induced angiogenesis by disruption
of PI3K/Akt signaling. 相似文献
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Aim
This study investigated the effects of pigment epithelium-derived factor (PEDF) on advanced glycation end-product (AGE)-induced cytotoxicity in porcine retinal pericytes and the signalling mechanism involved.Methods
Retinal pericytes were isolated from porcine eyes and characterized by immunocytochemistry. The effect of AGEs and PEDF on cell proliferation was determined by bromodeoxyuridine (BrdU) assay. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was analyzed by luminescence assay. Reactive oxygen species (ROS), nitric oxide (NO), superoxide dismutase (SOD) and glutathione peroxidase (GSH) were determined by biochemical assays. Induction of apoptosis was determined by caspase-3 colorimetric assay and DNA fragmentation analysis. Src activity was assessed by transient transfection analysis, and the status of Src phosphorylation at Y419 was analyzed by a competitive ELISA method.Results
AGEs significantly increased intracellular ROS generation in pericytes via NADPH oxidase and induced cell death via caspase-3 enzyme activation, whereas PEDF increased cell proliferation in a dose-dependent manner. In addition, PEDF inhibited AGE-induced ROS generation by increasing levels of SOD and GSH, and also blocked the activation of caspase-3. Furthermore, PEDF induced cell survival via the Src pathway by Src phosphorylation at Y419, as evidenced by a pharmacological inhibitor and Src mutants.Conclusion
These results suggest that PEDF abrogates AGE-induced oxidative stress and apoptosis in retinal pericytes via the Src pathway, thereby suggesting that PEDF is an effective therapeutic agent for the treatment of loss of pericytes in early diabetic retinopathy. 相似文献9.
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