scholarly journals LRG1 as a novel therapeutic target in eye disease

Eye ◽  
2022 ◽  
Author(s):  
Giulia De Rossi ◽  
Marlene E. Da Vitoria Lobo ◽  
John Greenwood ◽  
Stephen E. Moss
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Age Related Macular Degeneration ◽  
New Drugs ◽  
High Rate ◽  
Eye Disease ◽  
Ageing Population ◽  
Age Related ◽  
Number Of Patients

AbstractRetinal and choroidal diseases are major causes of blindness and visual impairment in the developed world and on the rise due to an ageing population and diabetes epidemic. Standard of care is centred around blockade of vascular endothelial growth factor (VEGF), but despite having halved the number of patients losing sight, a high rate of patient non-response and loss of efficacy over time are key challenges. Dysregulation of vascular homoeostasis, coupled with fibrosis and inflammation, are major culprits driving sight-threatening eye diseases. Improving our knowledge of these pathological processes should inform the development of new drugs to address the current clinical challenges for patients. Leucine-rich α-2 glycoprotein 1 (LRG1) is an emerging key player in vascular dysfunction, inflammation and fibrosis. Under physiological conditions, LRG1 is constitutively expressed by the liver and granulocytes, but little is known about its normal biological function. In pathological scenarios, such as diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD), its expression is ectopically upregulated and it acquires a much better understood pathogenic role. Context-dependent modulation of the transforming growth-factor β (TGFβ) pathway is one of the main activities of LRG1, but additional roles have recently been emerging. This review aims to highlight the clinical and pre-clinical evidence for the pathogenic contribution of LRG1 to vascular retinopathies, as well as extrapolate from other diseases, functions which may be relevant to eye disease. Finally, we will provide a current update on the development of anti-LRG1 therapies for the treatment of nvAMD.

scholarly journals Cell–Matrix Interactions in the Eye: From Cornea to Choroid

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 687
Author(s):  
Andrew E. Pouw ◽  
Mark A. Greiner ◽  
Razek G. Coussa ◽  
Chunhua Jiao ◽  
Ian C. Han ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Transforming Growth Factor Β ◽  
Corneal Dystrophy ◽  
Tissue Growth ◽  
Age Related Macular Degeneration ◽  
Disease States ◽  
Age Related

The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure maintenance, and vascular signaling. This review focuses on the interactions of the ECM for homeostasis of normal physiologic functions of the cornea, vitreous, retina, retinal pigment epithelium, Bruch’s membrane, and choroid as well as trabecular meshwork, optic nerve, conjunctiva and tenon’s layer as it relates to glaucoma. A variety of pathways and key factors related to ECM in the eye are discussed, including but not limited to those related to transforming growth factor-β, vascular endothelial growth factor, basic-fibroblastic growth factor, connective tissue growth factor, matrix metalloproteinases (including MMP-2 and MMP-9, and MMP-14), collagen IV, fibronectin, elastin, canonical signaling, integrins, and endothelial morphogenesis consistent of cellular activation-tubulogenesis and cellular differentiation-stabilization. Alterations contributing to disease states such as wound healing, diabetes-related complications, Fuchs endothelial corneal dystrophy, angiogenesis, fibrosis, age-related macular degeneration, retinal detachment, and posteriorly inserted vitreous base are also reviewed.

scholarly journals Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Karis Little ◽  
Maria Llorián-Salvador ◽  
Miao Tang ◽  
Xuan Du ◽  
Stephen Marry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Macular Degeneration ◽  
Transforming Growth Factor ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Two Stage ◽  
Blocking Antibody ◽  
Age Related ◽  
Subretinal Fibrosis ◽  
Isolectin B4

Abstract Background Macular fibrosis causes irreparable vision loss in neovascular age-related macular degeneration (nAMD) even with anti-vascular endothelial growth factor (VEGF) therapy. Inflammation is known to play an important role in macular fibrosis although the underlying mechanism remains poorly defined. The aim of this study was to understand how infiltrating macrophages and complement proteins may contribute to macular fibrosis. Methods Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser protocol developed by our group. The eyes were collected at 10, 20, 30 and 40 days after the second laser and processed for immunohistochemistry for infiltrating macrophages (F4/80 and Iba-1), complement components (C3a and C3aR) and fibrovascular lesions (collagen-1, Isolectin B4 and α-SMA). Human retinal sections with macular fibrosis were also used in the study. Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were treated with recombinant C3a, C5a or TGF-β for 48 and 96 h. qPCR, Western blot and immunohistochemistry were used to examine the expression of myofibroblast markers. The involvement of C3a-C3aR pathway in macrophage to myofibroblast transition (MMT) and subretinal fibrosis was further investigated using a C3aR antagonist (C3aRA) and a C3a blocking antibody in vitro and in vivo. Results Approximately 20~30% of F4/80+ (or Iba-1+) infiltrating macrophages co-expressed α-SMA in subretinal fibrotic lesions both in human nAMD eyes and in the mouse model. TGF-β and C3a, but not C5a treatment, significantly upregulated expression of α-SMA, fibronectin and collagen-1 in BMDMs. C3a-induced upregulation of α-SMA, fibronectin and collagen-1 in BMDMs was prevented by C3aRA treatment. In the two-stage laser model of induced subretinal fibrosis, treatment with C3a blocking antibody but not C3aRA significantly reduced vascular leakage and Isolectin B4+ lesions. The treatment did not significantly alter collagen-1+ fibrotic lesions. Conclusions MMT plays a role in macular fibrosis secondary to nAMD. MMT can be induced by TGF-β and C3a but not C5a. Further research is required to fully understand the role of MMT in macular fibrosis. Graphical abstract Macrophage to myofibroblast transition (MMT) contributes to subretinal fibrosis. Subretinal fibrosis lesions contain various cell types, including macrophages and myofibroblasts, and are fibrovascular. Myofibroblasts are key cells driving pathogenic fibrosis, and they do so by producing excessive amount of extracellular matrix proteins. We have found that infiltrating macrophages can transdifferentiate into myofibroblasts, a phenomenon termed macrophage to myofibroblast transition (MMT) in macular fibrosis. In addition to TGF-β1, C3a generated during complement activation in CNV can also induce MMT contributing to macular fibrosis. RPE = retinal pigment epithelium. BM = Bruch’s membrane. MMT = macrophage to myofibroblast transition. TGFB = transforming growth factor β. a-SMA = alpha smooth muscle actin. C3a = complement C3a.

scholarly journals Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Claudio Campa ◽  
Ciro Costagliola ◽  
Carlo Incorvaia ◽  
Carl Sheridan ◽  
Francesco Semeraro ◽  
...  
Keyword(s):  
Growth Factor ◽  
Choroidal Neovascularization ◽  
Inflammatory Mediators ◽  
Transforming Growth Factor ◽  
Pathological Condition ◽  
Inflammatory Cells ◽  
Angiogenic Factors ◽  
Age Related Macular Degeneration ◽  
Therapeutic Implications ◽  
Age Related

Choroidal neovascularization (CNV) is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed.

HtrA1: a novel regulator of physiological and pathological matrix mineralization?

2007 ◽  
Vol 35 (4) ◽  
pp. 669-671 ◽  
Author(s):  
A.E. Canfield ◽  
K.D. Hadfield ◽  
C.F. Rock ◽  
E.C. Wylie ◽  
F.L. Wilkinson
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Matrix Gla Protein ◽  
Age Related Macular Degeneration ◽  
Matrix Mineralization ◽  
Age Related ◽  
Morphogenetic Protein ◽  
Serine Protease Activity ◽  
Bmp Signalling

HtrA1 (high-temperature requirement protein A1) is a secreted multidomain protein with proven serine protease activity and the ability to regulate TGF-β (transforming growth factor-β)/BMP (bone morphogenetic protein) signalling. There is increasing evidence that HtrA1 regulates several pathological processes, including tumour development, Alzheimer's disease, age-related macular degeneration and osteoarthritis, although the mechanism(s) by which it regulates these processes have not been fully elucidated. Using overexpression and knock-down strategies, we have evidence demonstrating that HtrA1 is also a key regulator of physiological and pathological matrix mineralization in vitro. We propose that HtrA1 regulates mineralization by inhibiting TGF-β/BMP signalling and/or by cleaving specific matrix proteins, including decorin and MGP (matrix Gla protein). Taken together, these studies suggest that HtrA1 may be a novel therapeutic target for several diseases.

scholarly journals TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1360
Author(s):  
Anja Schlecht ◽  
Mario Vallon ◽  
Nicole Wagner ◽  
Süleyman Ergün ◽  
Barbara M. Braunger
Keyword(s):  
Tissue Damage ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Age Related Macular Degeneration ◽  
Retinal Tissue ◽  
Age Related ◽  
Retinal Blood Vessels ◽  
Secondary Tissue ◽  
The Individual ◽  
Neurotrophin Signaling

Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain.

Features of angiogenesis in eye diseases

2021 ◽  
Vol 25 (2) ◽  
pp. 106-113
Author(s):  
T. A. Khalimov
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Macular Degeneration ◽  
Transforming Growth Factor ◽  
Eye Diseases ◽  
Age Related Macular Degeneration ◽  
Published Data ◽  
Vascular Endothelial ◽  
Age Related ◽  
Endothelial Growth Factor

Based on the analysis of published data, the review provides information on the role and mechanisms of angiogenesis in the development of eye diseases. It has been shown that the developing inflammatory process associated with infections or damage to the organ of vision almost always leads to the appearance of newly formed vessels in the avascular cornea. The progression, in particular, of age-related macular degeneration is associated with the immune-mediated development of angiogenesis processes. A key inducer of angiogenesis is vascular endothelial growth factor (VEGF), whose activity can be enhanced by a number of pro-inflammatory cytokines (tumor necrosis factor alpha, TNF-), growth (fibroblast growth factor, FGF) and transforming factors (transforming growth factor beta, TGF- ). In addition, VEGF overproduction is mediated by an imbalance of pro-angiogenic (angiogenin) and anti-angiogenic (angiostatin, vasostatin, endostatin; tissue inhibitors of matrix metalloproteinases) factors. Antiangiogenic activity based on inhibition of vascular endothelial growth factor (VEGF) has been successfully used in the treatment of a number of eye diseases, such as exudative age-related macular degeneration and diabetic macular edema, the pathogenesis of which is based on the growth of newly formed vessels. The review presents information on the main anti-angiogenic drugs for intravitreal administration, used in ophthalmology.

scholarly journals Age-related loss of the transforming growth factor β receptor ALK5 precedes osteoarthritis development in cartilage

2014 ◽  
Vol 22 ◽  
pp. S57
Author(s):  
A. van Caam ◽  
E. Blaney Davidson ◽  
E. Thijssen ◽  
W. van den Berg ◽  
P. van der Kraan
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Age Related ◽  
Β Receptor

scholarly journals Dual Roles of the AMP-Activated Protein Kinase Pathway in Angiogenesis

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 752 ◽  
Author(s):  
Li ◽  
Sun ◽  
Zou ◽  
Ying ◽  
Luo
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Stress Responses ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Age Related Macular Degeneration ◽  
Transcription Activator ◽  
Age Related ◽  
Amp Activated Protein Kinase

Angiogenesis plays important roles in development, stress response, wound healing, tumorigenesis and cancer progression, diabetic retinopathy, and age-related macular degeneration. It is a complex event engaging many signaling pathways including vascular endothelial growth factor (VEGF), Notch, transforming growth factor-beta/bone morphogenetic proteins (TGF-β/BMPs), and other cytokines and growth factors. Almost all of them eventually funnel to two crucial molecules, VEGF and hypoxia-inducing factor-1 alpha (HIF-1α) whose expressions could change under both physiological and pathological conditions. Hypoxic conditions stabilize HIF-1α, while it is upregulated by many oncogenic factors under normaxia. HIF-1α is a critical transcription activator for VEGF. Recent studies have shown that intracellular metabolic state participates in regulation of sprouting angiogenesis, which may involve AMP-activated protein kinase (AMPK). Indeed, AMPK has been shown to exert both positive and negative effects on angiogenesis. On the one hand, activation of AMPK mediates stress responses to facilitate autophagy which stabilizes HIF-1α, leading to increased expression of VEGF. On the other hand, AMPK could attenuate angiogenesis induced by tumor-promoting and pro-metastatic factors, such as the phosphoinositide 3-kinase /protein kinase B (Akt)/mammalian target of rapamycin (PI3K/Akt/mTOR), hepatic growth factor (HGF), and TGF-β/BMP signaling pathways. Thus, this review will summarize research progresses on these two opposite effects and discuss the mechanisms behind the discrepant findings.

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