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Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 21428

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Special Issue Editors

Prof. Dr. Sarah Xin Zhang

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Guest Editor

Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York (SUNY), Buffalo, NY, USA
Interests: retinal disease; angiogenesis; inflammation; stress signaling; neurodegeneration; neuroprotection

Dr. Joshua Jianxin Wang

E-Mail Website
Co-Guest Editor

Department of Ophthalmology, Jacobs School of Medicine & Biomedical Sciences, SUNY-Buffalo, New York 14215, USA
Interests: diabetic retinopathy; diabetic vascular disease; insulin resistance and diabetic nephropathy; retina; peripheral vessel and kidney

Special Issue Information

Dear Colleagues,

Angiogenesis is a fundamental biological process in which new capillary blood vessels are formed by sprouting or splitting from pre-existing ones. While physiological angiogenesis plays an essential role in the development of retinal vasculature, uncontrolled new vessel growth resulting in retinal dysfunction and damage is a major cause of vision loss in common retinal diseases such as diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration. In contrast to mature blood vessels, the pathological new vessels are malstructured and hyperpermeable, resulting in retinal exudates, edema, hemorrhage, and immune cell infiltration. Furthermore, recent research suggests that endothelial cells themselves can function as a type of innate immune cells. Under pathological conditions such as diabetic retinopathy, activated endothelial cells express and secret inflammatory cytokines that attract macrophages and leukocytes, which, in turn, exacerbate retinal inflammation and promote angiogenesis. Inflammation also plays a central role in retinal neurodegeneration that ultimately leads to blindness. Understanding the molecular and cellular mechanisms of angiogenesis and inflammation in retinal diseases is therefore critical for developing new therapeutic interventions to preserve vision.

This Special Issue entitled “Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases” solicits original research and review articles that illustrate new findings on the topics of retinal angiogenesis and inflammation and provide mechanistic insights into pathogenesis of retinal diseases. We anticipate that these contributions will not only help in advancing our understanding and knowledge of signaling pathways that regulate the complex interplay of angiogenesis and inflammation but also facilitate the discovery of new treatment for retinal diseases.

Prof. Dr. Sarah Xin Zhang
Dr. Joshua Jianxin Wang
Guest Editors

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Keywords

Angiogenesis
Inflammation
Retina
Endothelial cells
Neovascularization
Diabetic retinopathy
Age-related macular degeneration
Retinopathy of prematurity

Published Papers (11 papers)

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Research

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15 pages, 9073 KiB

Open AccessArticle

Limited Hyperoxia-Induced Proliferative Retinopathy (LHIPR) as a Model of Retinal Fibrosis, Angiogenesis, and Inflammation

by Katia Corano Scheri, Yi-Wen Hsieh, Eunji Jeong and Amani A. Fawzi

Cells 2023, 12(20), 2468; https://doi.org/10.3390/cells12202468 - 17 Oct 2023

Viewed by 1071

Abstract

The progression to fibrosis and traction in retinopathy of prematurity (ROP) and other ischemic retinopathies remains an important clinical and surgical challenge, necessitating a comprehensive understanding of its pathogenesis. Fibrosis is an unbalanced deposition of extracellular matrix components responsible for scar tissue formation with consequent tissue and organ impairment. Together with retinal traction, it is among the main causes of retinal detachment and vision loss. We capitalize on the Limited Hyperoxia Induced Retinopathy (LHIPR) model, as it reflects the more advanced pathological phenotypes seen in ROP and other ischemic retinopathies. To model LHIPR, we exposed wild-type C57Bl/6J mouse pups to 65% oxygen from P0 to P7. Then, the pups were returned to room air to recover until later endpoints. We performed histological and molecular analysis to evaluate fibrosis progression, angiogenesis, and inflammation at several time points, from 1.5 months to 9 months. In addition, we performed in vivo retinal imaging by optical coherence tomography (OCT) or OCT Angiography (OCTA) to follow the fibrovascular progression in vivo. Although the retinal morphology was relatively preserved, we found a progressive increase in preretinal fibrogenesis over time, up to 9 months of age. We also detected blood vessels in the preretinal space as well as an active inflammatory process, altogether mimicking advanced preretinal fibrovascular disease in humans. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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14 pages, 5640 KiB

Open AccessArticle

Bone Morphogenetic Protein-4 Impairs Retinal Endothelial Cell Barrier, a Potential Role in Diabetic Retinopathy

by Noureldien H. E. Darwish, Khaled A. Hussein, Khaled Elmasry, Ahmed S. Ibrahim, Julia Humble, Mohamed Moustafa, Fatma Awadalla and Mohamed Al-Shabrawey

Cells 2023, 12(9), 1279; https://doi.org/10.3390/cells12091279 - 28 Apr 2023

Viewed by 1474

Abstract

Bone Morphogenetic Protein 4 (BMP4) is a secreted growth factor of the Transforming Growth Factor beta (TGFβ) superfamily. The goal of this study was to test whether BMP4 contributes to the pathogenesis of diabetic retinopathy (DR). Immunofluorescence of BMP4 and the vascular marker isolectin-B4 was conducted on retinal sections of diabetic and non-diabetic human and experimental mice. We used Akita mice as a model for type-1 diabetes. Proteins were extracted from the retina of postmortem human eyes and 6-month diabetic Akita mice and age-matched control. BMP4 levels were measured by Western blot (WB). Human retinal endothelial cells (HRECs) were used as an in vitro model. HRECs were treated with BMP4 (50 ng/mL) for 48 h. The levels of phospho-smad 1/5/9 and phospho-p38 were measured by WB. BMP4-treated and control HRECs were also immunostained with anti-Zo-1. We also used electric cell-substrate impedance sensing (ECIS) to calculate the transcellular electrical resistance (TER) under BMP4 treatment in the presence and absence of noggin (200 ng/mL), LDN193189 (200 nM), LDN212854 (200 nM) or inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2; SU5416, 10 μM), p38 (SB202190, 10 μM), ERK (U0126, 10 μM) and ER stress (Phenylbutyric acid or PBA, 30 μmol/L). The impact of BMP4 on matrix metalloproteinases (MMP2 and MMP9) was also evaluated using specific ELISA kits. Immunofluorescence of human and mouse eyes showed increased BMP4 immunoreactivity, mainly localized in the retinal vessels of diabetic humans and mice compared to the control. Western blots of retinal proteins showed a significant increase in BMP4 expression in diabetic humans and mice compared to the control groups (p < 0.05). HRECs treated with BMP4 showed a marked increase in phospho-smad 1/5/9 (p = 0.039) and phospho-p38 (p = 0.013). Immunofluorescence of Zo-1 showed that BMP4-treated cells exhibited significant barrier disruption. ECIS also showed a marked decrease in TER of HRECs by BMP4 treatment compared to vehicle-treated HRECs (p < 0.001). Noggin, LDN193189, LDN212854, and inhibitors of p38 and VEGFR2 significantly mitigated the effects of BMP4 on the TER of HRECs. Our finding provides important insights regarding the role of BMP4 as a potential player in retinal endothelial cell dysfunction in diabetic retinopathy and could be a novel target to preserve the blood–retinal barrier during diabetes. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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17 pages, 1568 KiB

Open AccessArticle

Peripheral Blood Mononuclear Cells from Patients with Type 1 Diabetes and Diabetic Retinopathy Produce Higher Levels of IL-17A, IL-10 and IL-6 and Lower Levels of IFN-γ—A Pilot Study

by Gideon Obasanmi, Noemi Lois, David Armstrong, Jose M. Romero Hombrebueno, Aisling Lynch, Mei Chen and Heping Xu

Cells 2023, 12(3), 467; https://doi.org/10.3390/cells12030467 - 31 Jan 2023

Cited by 4 | Viewed by 2617

Abstract

Inflammation is key to the pathogenesis of diabetic retinopathy (DR). This prospective study investigated alterations in inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) in 41 people with type 1 diabetes (T1D), sub-grouped into mild non-proliferative DR (mNPDR; n = 13) and active and inactive (each n = 14) PDR. Age/gender-matched healthy controls (n = 13) were included. PBMCs were isolated from blood samples. Intracellular cytokine expression by PBMCs after 16-h stimulation (either E. coli lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate plus ionomycin, D-glucose or D-mannitol) were assessed by flow cytometry. Cytokine production in plasma, non-stimulated and LPS-stimulated PBMC supernatant was also assessed. Increased BMC IL-10 secretion and reduced expression of IL-6 and IFN-γ in CD3⁺ cells were observed in mNPDR. Reduced IL-6 and IL-10 secretion, and higher levels of intracellular IL-6 expression, especially in CD11b⁺ PBMCs, was detected in aPDR; levels were positively correlated with DR duration. Patients with T1D demonstrated increased intracellular expression of IL-17A in myeloid cells and reduced IFN-γ expression in CD3⁺ cells. Plasma levels of IL-1R1 were increased in mNPDR compared with controls. Results suggest that elevated PBMC-released IL-10, IL-6, in particular myeloid-produced IL-17A, may be involved in early stages of DR. IL-6-producing myeloid cells may play a role in PDR development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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16 pages, 4998 KiB

Open AccessArticle

Hematopoietic Cells Influence Vascular Development in the Retina

by Bright Asare-Bediako, Yvonne Adu-Agyeiwaah, Antonio Abad, Sergio Li Calzi, Jason L. Floyd, Ram Prasad, Mariana DuPont, Richmond Asare-Bediako, Xose R. Bustelo and Maria B. Grant

Cells 2022, 11(20), 3207; https://doi.org/10.3390/cells11203207 - 13 Oct 2022

Cited by 2 | Viewed by 1451

Abstract

Hematopoietic cells play a crucial role in the adult retina in health and disease. Monocytes, macrophages, microglia and myeloid angiogenic cells (MACs) have all been implicated in retinal pathology. However, the role that hematopoietic cells play in retinal development is understudied. The temporal changes in recruitment of hematopoietic cells into the developing retina and the phenotype of the recruited cells are not well understood. In this study, we used the hematopoietic cell-specific protein Vav1 to track and investigate hematopoietic cells in the developing retina. By flow cytometry and immunohistochemistry, we show that hematopoietic cells are present in the retina as early as P0, and include microglia, monocytes and MACs. Even before the formation of retinal blood vessels, hematopoietic cells localize to the inner retina where they eventually form networks that intimately associate with the developing vasculature. Loss of Vav1 lead to a reduction in the density of medium-sized vessels and an increased inflammatory response in retinal astrocytes. When pups were subjected to oxygen-induced retinopathy, hematopoietic cells maintained a close association with the vasculature and occasionally formed ‘frameworks’ for the generation of new vessels. Our study provides further evidence for the underappreciated role of hematopoietic cells in retinal vasculogenesis and the formation of a healthy retina. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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19 pages, 4080 KiB

Open AccessArticle

Proteomic Analysis of Retinal Mitochondria-Associated ER Membranes Identified Novel Proteins of Retinal Degeneration in Long-Term Diabetes

by Joshua J. Wang, Karen Sophia Park, Narayan Dhimal, Shichen Shen, Xixiang Tang, Jun Qu and Sarah X. Zhang

Cells 2022, 11(18), 2819; https://doi.org/10.3390/cells11182819 - 09 Sep 2022

Cited by 6 | Viewed by 2213

Abstract

The mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) is the physical contact site between the ER and the mitochondria and plays a vital role in the regulation of calcium signaling, bioenergetics, and inflammation. Disturbances in these processes and dysregulation of the ER and mitochondrial homeostasis contribute to the pathogenesis of diabetic retinopathy (DR). However, few studies have examined the impact of diabetes on the retinal MAM and its implication in DR pathogenesis. In the present study, we investigated the proteomic changes in retinal MAM from Long Evans rats with streptozotocin-induced long-term Type 1 diabetes. Furthermore, we performed in-depth bioinformatic analysis to identify key MAM proteins and pathways that are potentially implicated in retinal inflammation, angiogenesis, and neurodegeneration. A total of 2664 unique proteins were quantified using IonStar proteomics-pipeline in rat retinal MAM, among which 179 proteins showed significant changes in diabetes. Functional annotation revealed that the 179 proteins are involved in important biological processes such as cell survival, inflammatory response, and cellular maintenance, as well as multiple disease-relevant signaling pathways, e.g., integrin signaling, leukocyte extravasation, PPAR, PTEN, and RhoGDI signaling. Our study provides comprehensive information on MAM protein changes in diabetic retinas, which is helpful for understanding the mechanisms of metabolic dysfunction and retinal cell injury in DR. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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24 pages, 5234 KiB

Open AccessArticle

Nuclear Receptor Atlases of Choroidal Tissues Reveal Candidate Receptors Associated with Age-Related Macular Degeneration

by Jeremy Peavey, Vipul M. Parmar and Goldis Malek

Cells 2022, 11(15), 2386; https://doi.org/10.3390/cells11152386 - 02 Aug 2022

Cited by 5 | Viewed by 2011 | Correction

Abstract

The choroid is a vulnerable tissue site in the eye, impacted in several blinding diseases including age related macular degeneration (AMD), which is the leading cause of central vision loss in the aging population. Choroidal thinning and choriocapillary dropout are features of the early form of AMD, and endothelial dysfunction and vascular changes are primary characteristics of the neovascular clinical sub-type of AMD. Given the importance, the choroidal endothelium and outer vasculature play in supporting visual function, a better understanding of baseline choroidal signaling pathways engaged in tissue and cellular homeostasis is needed. Nuclear receptors are a large family of transcription factors responsible for maintaining various cellular processes during development, aging and disease. Herein we developed a comprehensive nuclear receptor atlas of human choroidal endothelial cells and freshly isolated choroidal tissue by examining the expression levels of all members of this transcription family using quantitative real time PCR. Given the close relationship between the choroid and retinal pigment epithelium (RPE), this data was cross-referenced with the expression profile of nuclear receptors in human RPE cells, to discover potential overlap versus cell-specific nuclear receptor expression. Finally, to identify candidate receptors that may participate in the pathobiology of AMD, we cataloged nuclear receptor expression in a murine model of wet AMD, from which we discovered a subset of nuclear receptors differentially regulated following neovascularization. Overall, these databases serve as useful resources establishing the influence of nuclear receptor signaling pathways on the outer vascular tissue of the eye, while providing a list of receptors, for more focused investigations in the future, to determine their suitability as potential therapeutic targets for diseases, in which the choroid is affected. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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16 pages, 904 KiB

Open AccessArticle

VEGFA Haplotype and VEGF-A and VEGF-R2 Protein Associations with Exudative Age-Related Macular Degeneration

by Alvita Vilkeviciute, Dzastina Cebatoriene, Loresa Kriauciuniene and Rasa Liutkeviciene

Cells 2022, 11(6), 996; https://doi.org/10.3390/cells11060996 - 15 Mar 2022

Cited by 2 | Viewed by 1980

Abstract

Our study aimed to reveal the associations between VEGFA SNPs (rs1570360, rs699947, rs3025033, and rs2146323), their haplotypes, VEGF-A and VEGF-R2 serum concentrations, and early and exudative AMD. A total of 339 subjects with early AMD and 419 with exudative AMD groups, and 374 healthy subjects, were genotyped for four VEGFA SNPs (rs1570360, rs699947, rs3025033, and rs2146323). VEGF-A and VEGFR-2 serum concentrations were measured in exudative AMD and controls. The results revealed that rs3025033 G allele was significantly associated with lower odds of exudative AMD under the dominant model (OR = 0.67; 95% CI: 0.49–0.80; p = 0.0088) and additive (OR = 0.7; 95% CI: 0.54–0.90; p = 0.0058) models after Bonferroni correction. In the female group, rs3025033 AG genotype was associated with exudative AMD under the codominant model (OR = 0.57; 95% CI: 0.37–0.87; p = 0.009) and G allele under the dominant (OR = 0.55; 95% CI: 0.37–0.82; p = 0.0032) and additive models (OR = 0.60; 95% CI: 0.42–0.84; p = 0.0028). Haplotype analysis revealed that individuals carrying rs1570360, rs699947, rs3025033, and rs2146323 haplotype A-A-G-A had decreased risk of exudative AMD (OR = 0.46, 95% CI: 0.23–0.90; p = 0.023). The VEGF-A and VEGF-R2 serum concentrations did not differ between study groups; we found that patients with exudative AMD carrying at least one C allele at rs699947 have statistically significantly higher VEGF-A serum concentrations compared to AA genotype carriers (485.95 (945.93) vs. 194.97 (-), respectively, p = 0.046). In conclusion, we found that VEGFA rs3025033 and haplotype rs1570360A-rs699947A-rs3025033G- rs2146323A play a protective role for exudative AMD in the Caucasian population. Furthermore, rs699947 is associated with elevated VEGF-A serum concentrations in exudative AMD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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Review

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46 pages, 4606 KiB

Open AccessReview

Assessment of Inner Blood–Retinal Barrier: Animal Models and Methods

by Kiran Bora, Neetu Kushwah, Meenakshi Maurya, Madeline C. Pavlovich, Zhongxiao Wang and Jing Chen

Cells 2023, 12(20), 2443; https://doi.org/10.3390/cells12202443 - 12 Oct 2023

Cited by 4 | Viewed by 2367

Abstract

Proper functioning of the neural retina relies on the unique retinal environment regulated by the blood–retinal barrier (BRB), which restricts the passage of solutes, fluids, and toxic substances. BRB impairment occurs in many retinal vascular diseases and the breakdown of BRB significantly contributes to disease pathology. Understanding the different molecular constituents and signaling pathways involved in BRB development and maintenance is therefore crucial in developing treatment modalities. This review summarizes the major molecular signaling pathways involved in inner BRB (iBRB) formation and maintenance, and representative animal models of eye diseases with retinal vascular leakage. Studies on Wnt/β-catenin signaling are highlighted, which is critical for retinal and brain vascular angiogenesis and barriergenesis. Moreover, multiple in vivo and in vitro methods for the detection and analysis of vascular leakage are described, along with their advantages and limitations. These pre-clinical animal models and methods for assessing iBRB provide valuable experimental tools in delineating the molecular mechanisms of retinal vascular diseases and evaluating therapeutic drugs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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14 pages, 1047 KiB

Open AccessReview

Cross Talks between Oxidative Stress, Inflammation and Epigenetics in Diabetic Retinopathy

by Renu A. Kowluru

Cells 2023, 12(2), 300; https://doi.org/10.3390/cells12020300 - 12 Jan 2023

Cited by 19 | Viewed by 2289

Abstract

Diabetic retinopathy, one of the most devastating complications of diabetes, is a multifactorial progressing disease with a very complex etiology. Although many metabolic, molecular, functional and structural changes have been identified in the retina and its vasculature, the exact molecular mechanism of its pathogenesis still remains elusive. Sustained high-circulating glucose increases oxidative stress in the retina and also activates the inflammatory cascade. Free radicals increase inflammatory mediators, and inflammation can increase production of free radicals, suggesting a positive loop between them. In addition, diabetes also facilitates many epigenetic modifications that can influence transcription of a gene without changing the DNA sequence. Several genes associated with oxidative stress and inflammation in the pathogenesis of diabetic retinopathy are also influenced by epigenetic modifications. This review discusses cross-talks between oxidative stress, inflammation and epigenetics in diabetic retinopathy. Since epigenetic changes are influenced by external factors such as environment and lifestyle, and they can also be reversed, this opens up possibilities for new strategies to inhibit the development/progression of this sight-threatening disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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16 pages, 1656 KiB

Open AccessReview

The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity

by Thaonhi Cung, Haibo Wang and M. Elizabeth Hartnett

Cells 2022, 11(12), 1951; https://doi.org/10.3390/cells11121951 - 17 Jun 2022

Cited by 4 | Viewed by 2257

Abstract

Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Angiogenesis and Inflammation in Retinal Diseases)

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