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Endothelial Wnt-Pathway Activation Protects the Blood-Retinal-Barrier

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Endothelial Wnt-Pathway Activation Protects the Blood-Retinal-Barrier Open Access Thrombosis & Haemostasis: Research Review Article Endothelial Wnt-Pathway Activation Protects the Blood- Retinal-Barrier during Neurodegeneration-Induced Vasoregression Kolibabka M1*, Acunman K1, Riemann S1, Huang H2, Gretz N3, Hoffmann S3, Feng Y2 and Hammes Abstract HP1,4 Vasoregression and impairment of the blood-retinal-barrier are hallmarks 15th Medical Department, Heidelberg University, Germany of diabetic retinopathy and especially the loss of pericytes is believed to be in 2Institute for Experimental Pharmacology and part responsible for increased capillary permeability. However, heterogeneity in Toxicology, Heidelberg University, Germany retinal permeability despite homogeneous pericyte loss raise doubts concerning 3Medical Research Center, Medical Faculty Mannheim, this responsibility. In this study, we identify the mechanisms preserving blood- Heidelberg University, Germany retinal barrier integrity despite the loss of pericytes. In male homozygous 4European Center for Angioscience (ECAS), Germany Polycystic Kidney Disease (PKD) rat, a model of neurodegeneration-induced *Corresponding author: Kolibabka M, 5th Medical vasoregression, we demonstrate the loss of pericytes without increased Department, Heidelberg University, Medical Faculty permeability by quantitative retina morphometry and immunofluorescence Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, staining. Expression profiling of adherens junction associated genes via Germany qPCR arrays revealed the up regulation of Wnt-pathway dependent factors as possible underlying mechanism. A gene regulatory network analysis Received: March 08, 2018; Accepted: April 27, 2018; identified the Lymphoid Enhancer binding Factor 1 (Lef1), a transcription factor Published: May 18, 2018 in non-canonical Wnt-signaling, as upstream effectors for the observed gene regulation. Lef1 expression was up regulated in PKD rats and repression of Lef1using siRNA resulted in increased permeability in Human Umbilical Vein Endothelial Cells (HUVECs) in vitro. Regulation of Lef1 gene expression during the course of vasoregression was mediated by a demethylation of the Lef1 promoter in PKD rats as demonstrated by methylation dependent qPCR. Our data demonstrate that capillary endothelial cells are able to preserve the integrity of the blood-retinal-barrier despite a loss of pericytes by promoter- demethylation and consecutive up regulation of Lef1. This novel principle may lead to new therapeutic approaches by targeting endothelial Lef1 in diseases with impaired vascular barriers. Keywords: Retinopathy; Pericyte loss; Wnt-pathway; Lymphoid enhancer binding factor 1; Vasoregression Abbreviations Increased capillary permeability in diabetic retinopathy primarily arises as response to increased levels of retinal Vascular Endothelial PKD: Polycystic Kidney Disease; qPCR: Quantitative Real Growth Factor (VEGF). However, the loss of pericytes is assumed Time Polymerase Chain Reaction; Wnt: Wingless-type MMTV an additional factor in the Breakdown of The Blood-Retinal-Barrier Integration Site Family; Lef1: lymphoid Enhancer binding Factor (BRB) [5-7]. 1; siRNA: small interfering Ribonucleic Acid; HUVEC: Human Umbilical Vein Endothelial Cell; BRB: Blood-Retinal Barrier; The polycystic kidney disease (CMV-HA-PKD2(1-703), PKD) VEGF - Vascular Endothelial Growth Factor; VE-Cadherin: rat is an experimental model for neurodegeneration-induced Vasculo-Endothelial cadherin; SD: Sprague Dawley; Cq: Cycle of vasoregression. Due to a primary degeneration of photoreceptor quantification; Hnf4a: Hepatocyte nuclear factor 4 alpha; TMB: cells, the retinal oxygen consumption decreases over the course of 3,3’,5,5’-Tetramethylbenzidine; gDNA: genomic Desoxyribonucleic the degeneration in the PKD rat [8,9]. Due to the reduced oxygen Acid; MMP2: Matrix Metalloproteinase 2. demand, the PKD retina does not develop ischemia, despite vasoregression. Without ischemia, the retinal VEGF levels in the Introduction PKD rat remain on low to normal levels, allowing the investigation Retinal degeneration in the pathogenesis of retinopathies affects of the impact of pericyte loss on blood-retinal permeability without every compartment of the neurovascular unit. The impairment of the influence of VEGF [10]. In contrast to a recently published study, the retinal vasculature is the basis of a variety of retinopathies, most in which a minor loss of pericytes was associated with a slightly prominently in forms of macular edema and in diabetic retinopathy increased capillary permeability, the vasoregression in the PKD [1]. Increased permeability, para- and transcellular, loss of pericytes rat is severely aggravated, leading to faster dynamics in vascular and formation of acellular capillaries are the most prominent vascular remodeling processes [11]. aberrations in the early phases of experimental retinopathies [2-4]. BRB integrity is dependent on a variety of factors, mainly Thromb Haemost Res - Volume 2 Issue 1 - 2018 Citation: Kolibabka M, Acunman K, Riemann S, Huang H, Gretz N, Hoffmann S, et al. Endothelial Wnt-Pathway Submit your Manuscript | www.austinpublishinggroup.com Activation Protects the Blood-Retinal-Barrier during Neurodegeneration-Induced Vasoregression. Thromb Kolibabka et al. © All rights are reserved Haemost Res. 2018; 2(1): 1010. Kolibabka M Austin Publishing Group Figure 2: Gene expression of adherens junction associated genes. (a) Figure 1: Vasoregression with preserved BRB integrity. (a) Increased Heatmap analysis of 84 adherens junction associated genes in 4 weeks old numbers of acellular capillaries in PKD rats from 4 weeks of age on. (left) and 8 weeks old (right) old SD and PKD rat retinae. Illustrated is up- Aggravating vasoregression in 8 weeks old PKD rats. (b) Pericyte numbers regulation (red) to down-regulation (green), PKD vs SD. (b) Volcano plot of are significantly reduced in PKD rats similarly at 4 and 8 weeks of age. (c) adherens junction associated genes in 4 weeks (left) and 8 weeks old (right) Albumin immunofluorescence stainings of vertical paraffin sections show no SD and PKD rat retinae. Red dashed lines indicate thresholds for significant sign of extravasated albumin in 8 weeks old SD and PKD rats. (a)+(b) n=4, (y-axis: p=0.05) and relevant regulation (x-axis: estimate= -0.5849 and ***p<0.001, #p<0.0001. (c) Scale bar=100µm. 0.5849 corresponding to a fold regulation= -1.5 and 1.5). inter-cellular junction molecules on different levels and capillary described [8]. The animals were kept in a 12 hours light-dark cycle blood flow, locally regulated by pericytes [7,12]. The inter-cellular with food and water ad libitum. At 4 and 8 weeks of age animals were communication within the endothelium and between endothelial cells killed, the eyes enucleated, snap-frozen in liquid nitrogen and stored and pericytes deserves special attention. Junctional components of at -80°C. Age-matched Sprague Dawley (SD) rats (https://www. note are inter-endothelial tight and adherens junctions and especially janvier-labs.com/rodent-research-models-services/research-models/ adherens junctions are connected to an intracellular signaling per-species/outbred-rats/product/sprague-dawley.html) served as network, which mediates endothelial-pericyte communication, too controls (Janvier Labs, Le Genest-Saint-Isle, France). All animal [13-17]. Whereas tight junctions represent a more restrictive barrier experiments were conducted in compliance with the EC directive than adherens junctions, the versatility of the later make them a 2010/63/EU, the guidelines of the statement for the use of Animals potential target for interventions in diabetic retinopathy [7]. Apart in Ophthalmic and Visual Research (ARVO) and have been reported from their physical resistance, adherens junction associated VE- following the ARRIVE guidelines. This study was approved by the cadherin acts as intracellular beta-caten in trap and is able to influence federal animal welfare committee (Regierungspräsidium Karlsruhe, the activity of Wnt-signaling pathways via the release of beta-catenin Karlsruhe, Germany). [18]. Altered Wnt-pathway activity is involved in the pathogenesis of diabetic retinopathy in patients and experimental models and, in Quantitative retina morphometry these models, has been linked to impaired VE-cadherin beta-catenin Quantitative retina morphometry was performed on retinal interactions [19-22]. In addition to Wnt-pathway activity, beta- digest preparations to analyze acellular capillaries and pericytes as catenin is involved in the regulation of Notch-signaling pathway previously published [27]. Investigators were simply blinded for activity via association with presenilin-1[23]. Notch-signaling is not quantification. only crucial in angiogenesis, but also in maintenance of vascular stability and barrier integrity by regulating adherens junctions [24- Albumin immunofluorescence 26]. Vertical 6µm paraffin sections were stained for rat albumin at 8 weeks of age. After deparaffinization, antigen retrieval was performed In this study, we analyze the mechanistic connections between using citrate buffer. Sections were rehydrated, permeabilized and BRB integrity and adherens junctions in a normoglycemic model of unspecific protein binding was blocked using 0.5% Triton X-100 neurodegeneration-induced vasoregression with negligible impact of (Sigma Aldrich, Steinheim, Germany) and 2% horse serum (Dako, VEGF signaling. Santa Clara, USA). Sections were incubated overnight at 4°C with Materials and Methods a sheep anti-rat albumin
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