Angiogenic Factors and Cytokines in Diabetic Retinopathy

Abcouwer, Steven F

doi:10.4172/2155-9899.s1-011

Cited by 71 publications

(90 citation statements)

References 100 publications

(122 reference statements)

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“…Activated microglia produce proinflammatory cytokines (e.g. VEGF and TNF-α) in early DR, promoting damage to the retinal neurons and vasculature [31]. To assess microglial activation, retinal flat mounts from db/db mice were co-labelled with isolectin B4 and Iba-1 [32] (ESM Fig.…”

Section: Resultsmentioning

confidence: 99%

Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes

Bhatta

Wang

et al. 2015

Diabetologia

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Aims/hypothesis Bone marrow-derived circulating angiogenic cells (CACs) play an important role in vascular repair. In diabetes, compromised functioning of the CACs contributes to the development of diabetic retinopathy; however, the underlying mechanisms are poorly understood. We examined whether endoplasmic reticulum (ER) stress, which has recently been linked to endothelial injury, is involved in diabetic angiogenic dysfunction. Methods Flow cytometric analysis was used to quantify bone marrow-derived progenitors (Lin−/c-Kit+/Sca-1+/CD34+) and blood-derived CACs (Sca-1+/CD34+) in 15-month-old Leprdb (db/db) mice and in their littermate control (db/+) mice used as a model of type 2 diabetes. Markers of ER stress in diabetic (db/db) and non-diabetic (db/+) bone marrow-derived early outgrowth cells (EOCs) and retinal vascular density were measured. Results The numbers of bone-marrow progenitors and CACs were significantly reduced in db/db mice. Vascular density was markedly decreased in the retinas of db/db mice, and this was accompanied by vascular beading. Microglial activation was enhanced, as was the production of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). The production of ER stress markers (glucose-regulated protein-78 [GRP-78], phosphorylated inositol-requiring enzyme-1α [p-IRE-1α], phosphorylated eukaryotic translation initiation factor-2α [p-eIF2α], activating transcription factor-4 [ATF4], C/EBP homologous protein [CHOP] and spliced X-box binding protein-1 [XBP1s] was significantly increased in bone marrow-derived EOCs from db/db mice. In addition, mouse EOCs cultured in high-glucose conditions demonstrated higher levels of ER stress, reduced colony formation, impaired migration and increased apoptosis, all of which were largely prevented by the chemical chaperone 4-phenylbutyrate. Conclusions/interpretation Taken together, our results indicate that diabetes increases ER stress in bone marrow angiogenic progenitor cells. Thus, targeting ER stress may offer a new approach to improving angiogenic progenitor cell function and promoting vascular repair in diabetes.

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Section: Resultsmentioning

confidence: 99%

Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes

Bhatta

Wang

et al. 2015

Diabetologia

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“…The key pharmacologic biomarker of CCR2 receptor antagonism, increases in MCP-1, was measured from peripheral blood samples, rather than sampling from vitreous fluid (vitrectomy), which in this study would have exposed the patient to risk. 41 However, the substantial rise in MCP-1 levels observed throughout the dosing period were similar to the maximum observed in healthy volunteers, which did not increase with higher doses of PF-04634817 (Pfizer data on file [NCT01098877 and NCT01140672]). Recent evaluation of another CCR2 inhibitor, CCX140-B, by de Zeeuw et al 43 in patients with type 2 diabetes and nephropathy also showed increases in serum MCP-1, but only at the highest dose studied.…”

Section: Discussionmentioning

confidence: 99%

“…As the relative contributions of multiple angiogenic and inflammatory factors associated with diabetic retinopathy/DME remain to be fully elucidated, 41 it is possible that CCR2/5 antagonism by PF-04634817 does not result in inhibition of a key pathway, or that the pathophysiologic function of these specific populations of receptors can be taken on by other mechanisms once CCR2/5 receptors are blocked.…”

Section: Discussionmentioning

confidence: 99%

A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema

Gale

Berger²,

Gilbert

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Citation: Gale JD, Berger B, Gilbert S, et al. A CCR2/5 inhibitor, PF-04634817, is inferior to monthly ranibizumab in the treatment of diabetic macular edema. Invest Ophthalmol Vis Sci. 2018;59:2659-2669. https://doi.org/10.1167/iovs.17-22731 PURPOSE. Ligands for the proinflammatory C-C chemokine receptor types 2 and 5 (CCR2 and CCR5) are elevated in the eyes of patients with diabetic macular edema (DME). We evaluated the efficacy and safety of PF-04634817, an oral CCR2/5 dual antagonist, versus intravitreal ranibizumab, in adult subjects with DME. METHODS.In this phase II, randomized, placebo-controlled, double-masked study, eligible subjects ( ‡18 years of age) had type 1 or 2 diabetes and DME with best-corrected visual acuity (BCVA) of 20/32 or worse (letter score 78), and up to 20/320 or better ( ‡24 letter score), in the study eye. Subjects were assigned randomly 1:1 to once-daily (QD) oral PF-04634817 200 mg plus masked sham therapy as placebo or monthly intravitreal ranibizumab 0.3/0.5 mg plus QD oral placebo. The primary objective was to evaluate the efficacy of PF-04634817 compared with ranibizumab in change from baseline in BCVA after 12 weeks in a noninferiority design. Noninferiority was based on BCVA 80% confidence interval (CI): there had to be a less than three letter loss in the PF-04634817 arm compared with the ranibizumab arm. RESULTS.A total of 199 subjects were randomized. Least squares mean difference in change in BCVA from baseline to week 12 in the study eye for the PF-04634817 arm was À2.41 letters (80% CI: À3.91, À0.91; P ¼ 0.04) compared with ranibizumab. PF-04634817 was well tolerated.CONCLUSIONS. Treatment with oral CCR2/5 receptor dual antagonist PF-04634817 was associated with a modest improvement in BCVA, but did not meet the predefined noninferiority criteria compared with intravitreal ranibizumab.

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“…3,4 Several studies have indicated that there is a significant increase in the levels of proangiogenic and proinflammatory factors and cytokines (e.g., vascular endothelial growth factor, IL-8, TNF-a, IL-6, and IL-1b) in the vitreous of a patient with diabetic retinopathy. [40][41][42][43] These findings have led to the emergence of several novel treatment modalities based on the administration of antivascular endothelial growth factor agents and corticosteroids to the diseased retina. 44,45 Corticosteroids are an attractive option due to their broad range of actions including anti-inflammatory and antiangiogenic effects.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Protein C–Targeting Liposomes Show Enhanced Uptake and Improved Therapeutic Efficacy in Human Retinal Endothelial Cells

Arta

Eriksen

Melander

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine whether human retinal endothelial cells (HRECs) express the endothelial cell protein C receptor (EPCR) and to realize its potential as a targeting moiety by developing novel single and dual corticosteroid-loaded functionalized liposomes that exhibit both enhanced uptake by HRECs and superior biologic activity compared to nontargeting liposomes and free drug.METHODS. EPCR expression of HRECs was investigated through flow cytometry and Western blot assays. EPCR-targeting liposomes were developed by functionalizing EPCR-specific antibodies onto liposomes, and the uptake of liposomes was assessed with flow cytometry and confocal laser scanning microscopy. The therapeutic potential of EPCR-targeting liposomes was determined by loading them with prednisolone either through bilayer insertion and/or by remote loading into the aqueous core. The carrier efficacy was assessed in two ways through its ability to inhibit secretion of interleukins in cells stimulated with high glucose and angiogenesis in vitro by using an endothelial cell tube formation assay. RESULTS.HRECs express EPCR at a similar level in both human aortic and umbilic vein endothelial cells. The EPCR-targeting liposomes displayed at least a 3-fold higher uptake compared to nontargeting liposomes. This enhanced uptake was translated into superior antiinflammatory efficacy, as the corticosteroid-loaded EPCR-targeting liposomes significantly reduced the secretion of IL-8 and IL-6 and inhibited the development of cell tube formations in contrast to nontargeting liposomes. CONCLUSIONS.We show that HRECs express EPCR and this receptor could be a promising nanomedicine target in ocular diseases where the endothelial barrier of the retina is compromised.

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Angiogenic Factors and Cytokines in Diabetic Retinopathy

Cited by 71 publications

References 100 publications

Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes

Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes

A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema

Endothelial Protein C–Targeting Liposomes Show Enhanced Uptake and Improved Therapeutic Efficacy in Human Retinal Endothelial Cells

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