Expression of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in sickle cell retina and choroid

Kim, Sahng Yeon; Mocanu, Carmen; McLeod, D. Scott; Bhutto, Imran Ahmed; Merges, Carol; Eid, Mark P.; Tong, Peter C.Y.; Lutty, Gerard A.

doi:10.1016/s0014-4835(03)00174-x

Cited by 68 publications

(47 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Kim et al 10 demonstrated that the levels of both PEDF and VEGF are elevated in the neovascular formations in eyes of patients with sickle cell retinopathy. They suggested that high levels of PEDF might play a role in inhibiting angiogenesis and inducing the regression of neovascularization.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Expression of Pigment Epithelium-Derived Factor and Vascular Endothelial Growth Factor in Fibrovascular Membranes from Patients with Proliferative Diabetic Retinopathy

et al. 2006

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…Kim et al 10 also reported that the most prominent expression of PEDF immunoreactivity is in the extracellular matrices. The strong expression of PEDF in the extracellular matrix of fibrovascular membranes may be related to the high affinity of PEDF for glycosaminoglycans and collagens.…”

mentioning

confidence: 96%

Expression of Pigment Epithelium-Derived Factor and Vascular Endothelial Growth Factor in Fibrovascular Membranes from Patients with Proliferative Diabetic Retinopathy

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Based on the solid evidence showing the inverse correlation between PEDF and VEGF levels in a variety of vascular diseases, we hypothesize that there exists a reciprocal regulation between these two major angiogenic regulators (Gao et al 2001, Ohno-Matsui et al 2001, Doll et al 2003, Kim et al 2003. In this study, we tested this hypothesis and explored the mechanisms by which PEDF regulates VEGF in retinal cells.…”

Section: Introductionmentioning

confidence: 94%

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Zhang¹,

Wang²,

Gao³

et al. 2006

Journal of Molecular Endocrinology

229

152

View full text Add to dashboard Cite

It has been shown that the balance between vascular endothelial growth factor (VEGF), a major angiogenic stimulator, and pigment epithelium-derived factor (PEDF), a potent angiogenic inhibitor, is critical for the regulation of vascular permeability and angiogenesis. However, the regulation of the balance is largely unclear. The present study demonstrated that there is a reciprocal interaction between VEGF and PEDF in the retina. PEDF significantly decreased VEGF expression in both retinal capillary endothelial cells (RCEC) and Mü ller cells. This PEDF effect was confirmed in the retina of rats with oxygen-induced retinopathy. Silencing of the PEDF gene by siRNA in Mü ller cells resulted in a significant upregulation of VEGF expression at both the RNA and protein levels, suggesting that PEDF is an endogenous negative regulator of VEGF. The further study of the mechanism showed that PEDF inhibited hypoxia-induced increases in VEGF promoter activity, HIF-1 nuclear translocation and mitogen activated protein kinase phosphorylation. These results suggest that PEDF inhibits VEGF expression at the transcriptional level. In addition, PEDF effectively inhibited VEGF binding to RCEC. Moreover, in vitro receptor-binding assay demonstrated that PEDF competed with VEGF for binding to VEGF receptor 2, which may represent a new mechanism for PEDF activity. On the other hand, VEGF significantly downregulated PEDF expression in RCEC, but not in retinal Mü ller cells, suggesting a VEGF receptormediated process. These results suggest that the reciprocal regulation between VEGF and PEDF may play a role in angiogenic control. The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes.

show abstract

“…[12][13][14][15][16] In addition, despite the heterogeneity of the SCD phenotype, several clinical manifestations associated with SCD, including proliferative retinopathy, pulmonary hypertension, leg ulcers and moyamoya syndrome, suggest an involvement of pathological angiogenic processes. [17][18][19][20][21][22][23][24] Although these observations indicate an angiogenic imbalance in SCD, the existence of pro-angiogenic mechanisms in SCD, and their consequences, remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

et al. 2015

View full text Add to dashboard Cite

ABSTRACTas a therapy in SCD. 25 Hydroxyurea is a cytostatic drug that inhibits ribonucleotide reductase, arresting cell division in the S-phase; additionally, data suggest that hydroxyurea can generate nitric oxide following administration. 26 We recently reported that hydroxyurea exerts anti-angiogenic effects in VEGF-dependent EC angiogenic in vitro assays and inhibits VEGF-dependent neovascularization in Matrigel implants in C57BL/6 mice. 27 This anti-angiogenic activity appears to be mediated by the down-regulation of endothelial hypoxia-inducible factor-1α (HIF-1α) expression, and consequent modulation of miRNA 221 expression, leading to the inhibition of EC proliferation and invasion/migration. 27To lend further support to the hypothesis of an unbalanced angiogenic state in SCD, we investigated the in vitro effects of plasma from patients with SCD on key steps of EC angiogenic behavior, namely, proliferative capability, invasive capacity and the formation of capillary-like EC structures. The plasma contents of angiogenic factors were associated with these data, as was the incidence of proliferative retinopathy in HbSC patients, a clinical manifestation thought to reflect augmented angiogenesis. 28The angiogenic activity of plasma from patients on hydroxyurea therapy was also examined. Finally, to confirm that SCD pathophysiology is associated with exacerbated angiogenesis, in vivo neovascularization was examined in a SCD mouse model, compared with non-SCD mice, utilizing a Matrigel plug angiogenesis assay. Methods PatientsPatients with HbSS or HbSC disease (collectively termed SCD) were recruited, during steady-state, at the Hematology Center, UNICAMP (Table 1). Details on the diagnosis of HbSS/HbSC, our definition of steady-state and criteria for commencing hydroxyurea therapy (15-30 mg hydroxyurea/kg/day) are given in the Online Supplementary Information. All patients had undergone ophthalmoscopy and fluorescein angiography for detection of proliferative retinopathy. A total of 29 HbSS patients, who did not have proliferative retinopathy, were recruited into the study. A total of 33 HbSC patients were recruited, of whom 16 did not have proliferative retinopathy (SC group) and 17 did (SCR group). One HbSC patient had been prescribed hydroxyurea following an ischemic stroke. Homozygous hemoglobin A (HbAA) healthy controls were age-and gender-matched, where possible. Informed written consent was obtained from all participants and the study was approved by the UNICAMP Ethics Committee, in accordance with national guidelines. Bioplex assayThe Fluorokine ® MAP, Human Angiogenesis Custom Premix Kit A (R&D Systems, Minneapolis, USA) was used to quantify Ang1, basic fibroblast growth factor (bFGF), PlGF, platelet-derived growth factor (PDGF)-AA, PDGF-BB, VEGF, VEGF-D, endostatin and thrombospondin-2 (TSP-2) in plasma, according to the manufacturer's instructions. The preparation of the plasma for the assay is described in the Online Supplementary Information. In vitro culture of human umbilical vein endothelial c...

show abstract

Expression of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in sickle cell retina and choroid

Cited by 68 publications

References 35 publications

Expression of Pigment Epithelium-Derived Factor and Vascular Endothelial Growth Factor in Fibrovascular Membranes from Patients with Proliferative Diabetic Retinopathy

Expression of Pigment Epithelium-Derived Factor and Vascular Endothelial Growth Factor in Fibrovascular Membranes from Patients with Proliferative Diabetic Retinopathy

Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF–VEGF receptor 2 binding in diabetic retinopathy

Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

Contact Info

Product

Resources

About