COMP-Ang1 Stabilizes Hyperglycemic Disruption of Blood-Retinal Barrier Phenotype in Human Retinal Microvascular Endothelial Cells

Rochfort, Keith D.; Carroll, Lara; Barabás, Péter; Curtis, Tine; Ambati, Balamurali K.; Barron, Niall; Cummins, Philip M.

doi:10.1167/iovs.19-27644

Cited by 6 publications

(3 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 2 , 4 Hyperglycemia has been shown to disrupt endothelial barrier properties and decrease the expression levels of VE-cadherin, ZO1, and occludin in HUVECs. 33 , 34 These findings are similar to our present findings. Although previous reports have suggested the targeting of LECT2 as a potential therapeutic strategy to inhibit tumor angiogenesis 17 and although neovascularization in DR is similar to that in tumors, 8 , 35 to date no work has been conducted to evaluate the functional relevance of LECT2 inhibition of DR progression or the underlying mechanisms.…”

Section: Discussionsupporting

confidence: 93%

LECT2 Ameliorates Blood–Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway

Qin

Xiao

Zheng

et al. 2022

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Purpose Current treatments for diabetic retinopathy (DR) have considerable limitations, emphasizing the need for new therapeutic options. The effect of leukocyte cell-derived chemotaxin 2 (LECT2) on diabetes-induced blood–retinal barrier impairment and the possible underlying mechanism were investigated both in vivo and in vitro. Methods Twenty diabetic and 22 nondiabetic eyes were included in this study. Additionally, we established a streptozotocin-induced diabetic mouse model and observed vascular leakage in mice treated with or without recombinant LECT2 (rLECT2) intravitreal injection (40 µg/mL, 1 µL). The levels of LECT2 and interendothelial junction proteins (ZO1, VE-cadherin, and occludin) were analyzed by western blot and/or immunofluorescence. Endothelial junctions in mouse retinas were observed by transmission electron microscopy (TEM). Moreover, confluent human retinal microvascular endothelial cells (HRMECs) and human umbilical vein endothelial cells (HUVECs) were treated (0–72 hours) with glucose (0 or 30 mM) in the presence or absence of rLECT2 (40–360 ng/mL). After treatment, intact cell monolayers were monitored for permeability to 40-kD FITC-dextran. Interendothelial junction targets and Tie2/Akt/mTOR signaling pathway components were investigated by western blot. Results In diabetic human and mouse retinas and high-glucose (30 mM)–treated HRMECs and HUVECs, the levels of LECT2 and interendothelial junction proteins were decreased. rLECT2 treatment (80 ng/mL) significantly attenuated the hyperglycemia-induced reduction in endothelial cell barrier function and inhibited the migration and tube formation of HRMECs and HUVECs. In addition, rLECT2 increased the levels of interendothelial junction proteins via activation of the Tie2/Akt/mTOR signaling pathway. Furthermore, intravitreal rLECT2 injections increased the levels of interendothelial junction proteins and reversed diabetes-induced junction disruption. Conclusions rLECT2 can increase the levels of interendothelial tight junction proteins through activation of the Tie2/Akt/mTOR signaling pathway and can ameliorate inner blood–retinal barrier impairment secondary to diabetes. LECT2 might be a potential target to prevent the progression of DR.

show abstract

Section: Discussionsupporting

confidence: 93%

LECT2 Ameliorates Blood–Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway

Qin

Xiao

Zheng

et al. 2022

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…To model microvascular changes caused by diabetes, we exposed iBRB MVNs to an elevated concentration of D-glucose (30 mM or 540 mg dl −1 ; grade 4 serum hyperglycemia corresponds to >500 mg dl −1 ) and pro-inflammatory cytokines TNF-α and IL-6 (1 ng ml −1 each) 47 . Vitreous and plasma levels of TNF-α and IL-6 are elevated in patients with DR and these pro-inflammatory cytokines were added to the high glucose medium to mimic the inflammatory state observed in diabetes [48][49][50][51] . Diabetic iBRB MVNs were examined on day 7 (D7), 14 (D14) and 28 (D28) to identify NPDR phenotypic changes compared to controls (Fig.…”

Section: Inducing Pathophysiological Phenotypes Associated With Diabe...mentioning

confidence: 99%

Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip

Maurissen,

Spielmann,

Schellenberg

et al. 2024

Nat Commun

View full text Add to dashboard Cite

Diabetic retinopathy (DR) is a microvascular disorder characterized by inner blood-retinal barrier (iBRB) breakdown and irreversible vision loss. While the symptoms of DR are known, disease mechanisms including basement membrane thickening, pericyte dropout and capillary damage remain poorly understood and interventions to repair diseased iBRB microvascular networks have not been developed. In addition, current approaches using animal models and in vitro systems lack translatability and predictivity to finding new target pathways. Here, we develop a diabetic iBRB-on-a-chip that produces pathophysiological phenotypes and disease pathways in vitro that are representative of clinical diagnoses. We show that diabetic stimulation of the iBRB-on-a-chip mirrors DR features, including pericyte loss, vascular regression, ghost vessels, and production of pro-inflammatory factors. We also report transcriptomic data from diabetic iBRB microvascular networks that may reveal drug targets, and examine pericyte-endothelial cell stabilizing strategies. In summary, our model recapitulates key features of disease, and may inform future therapies for DR.

show abstract

“…In the TJs of human dermal microvascular endothelial cells, claudin-5, but not occludin or other claudins, was mainly expressed and formed the intercellular barriers in dermal microvessels [18,19]. An engineered Ang-1 variant attenuated the hyperglycemia-induced reduced expressions of claudin-5, occludin, zonula occludens (ZO)-1, and vascular endothelial (VE)-cadherin in human retinal microvascular endothelial cells (HRMEC), which results in the recovery of HRMEC barrier function [20]. Thus, Ang-1 up-regulates the expressions of the TJ proteins claudin-5, occludin, and ZO-1 as well as the AJ protein VE-cadherin in HRMEC.…”

Section: Introductionmentioning

confidence: 99%

Mucopolysaccharide polysulfate promotes microvascular stabilization and barrier integrity of dermal microvascular endothelial cells via activation of the angiopoietin-1/Tie2 pathway

Fujiwara-Sumiyoshi

Ueda

Fujikawa

et al. 2021

Journal of Dermatological Science

View full text Add to dashboard Cite

Background: Mucopolysaccharide polysulfate (MPS) is a heparinoid and MPS-containing formulations are widely used as moisturizers for dry skin and to treat peripheral vascular insufficiency. Although MPS has therapeutic effects in skin diseases with microvascular abnormalities, the effects of MPS on microvascular function remain incompletely understood. Objective: The aim of this study was to evaluate the functional activities of MPS on human pericytes (HPC) and human dermal microvascular endothelial cells (HDMEC) in vitro, and on microvascular permeability of the skin. Methods: The protein expression of angiopoietin (Ang)-1 in HPC, and platelet-derived growth factor-BB (PDGF-BB) and phosphorylated tyrosine-protein kinase receptor 2 (Tie2) in HDMEC were measured in the presence or absence of MPS. The vascular barrier was evaluated by the expressions of claudin-5 and vascular endothelial (VE)-cadherin, and transendothelial electrical resistance (TEER). Results: In HPC, MPS dose-dependently enhanced Ang-1 secretion, which activated Tie2 in HDMEC. In HDMEC, MPS significantly increased the production of PDGF-BB, which is important for the recruitment of HPC to the vascular endothelium, and significantly increased the phosphorylation of Tie2, which results in the activation of the Ang-1/Tie2 signaling . MPS significantly increased the expression of tight junction protein claudin-5 and TEER in the HDMEC. Moreover, the intradermal injection of MPS prevented vascular endothelial growth factor-induced increase in vascular permeability in mouse skin. Conclusion:We found that MPS promoted microvascular stabilization and barrier integrity in HDMEC via Ang-1/Tie2 activation. These results suggest that MPS might improve microvascular abnormalities in various diseases accompanied by disturbances in Ang-1/Tie2 signaling.

show abstract

COMP-Ang1 Stabilizes Hyperglycemic Disruption of Blood-Retinal Barrier Phenotype in Human Retinal Microvascular Endothelial Cells

Cited by 6 publications

References 29 publications

LECT2 Ameliorates Blood–Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway

LECT2 Ameliorates Blood–Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway

Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip

Mucopolysaccharide polysulfate promotes microvascular stabilization and barrier integrity of dermal microvascular endothelial cells via activation of the angiopoietin-1/Tie2 pathway

Contact Info

Product

Resources

About