John Greenwood

John Greenwood
University College London | UCL · Institute of Ophthalmology

PhD FRCPath

About

225
Publications
23,146
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Introduction
The role of the vasculature in the pathogenesis of brain and retinal disease is a core focus of the Greenwood laboratory. We are investigating 1) endothelial cell mechanisms that facilitate the recruitment of leukocytes to the CNS, a critical step in the pathogenesis of diseases such as multiple sclerosis and posterior uveitis and 2) novel factors that contribute to vascular remodelling that occur in blinding diseases such as age-related macular degeneration and diabetic retinopathy.
Additional affiliations
January 1990 - present
University College London Institute of Ophthalmology
Position
  • Vascular biology, CNS inflammation, Retinal degeneration
January 1988 - December 1989
King's College London
Position
  • Blood-brain barrier
January 1979 - September 1987
Institute of Psychiatry
Position
  • Blood-brain barrier

Publications

Publications (225)
Article
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Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an app...
Article
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Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolate...
Article
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Retinal pathologies are frequently accompanied by retinal vascular responses, including the formation of new vessels by angiogenesis (neovascularization). Pathological vascular changes may also include less well characterized traits of vascular remodeling that are non-neovascular, such as vessel pruning and the emergence of dilated and tortuous ves...
Article
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Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that statins also have extensive immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therap...
Article
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Lymphocytes emigrate from the circulation to target tissues through the microvascular endothelial cell (EC) barrier. During paracellular transmigration cell-cell junctions have been proposed to disengage and provide homophilic and heterophilic interaction surfaces in a zip-like process. However, it is not known whether ECs modulate junction protein...
Article
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The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease...
Article
In recent years improving tumor vascular function, to render the tumour microenvironment less permissive and to improve delivery of therapeutics, has gained traction due to a growing body of supportive evidence. Identifying suitable targets that are tractable, ubiquitous and safe, however, has proven to be more challenging. Almost a decade ago we r...
Article
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The formation of new dysfunctional blood vessels is a crucial stage in the development of various conditions such as macular degeneration, diabetes, cardiovascular disease, neurological disease and inflammatory disorders, as well as during tumor growth, eventually contributing to metastasis. An important factor involved in pathogenic angiogenesis i...
Article
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Inflammation and fibrosis are important components of diseases that contribute to the malfunction of epithelia and endothelia. The Rho guanine nucleotide exchange factor (GEF) GEF-H1/ARHGEF-2 is induced in disease and stimulates inflammatory and fibrotic processes, cell migration, and metastasis. Here, we have generated peptide inhibitors to block...
Article
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Importance: It is a global challenge to provide regular retinal screening for all people with diabetes to detect sight-threatening diabetic retinopathy (STDR). Objective: To determine if circulating biomarkers could be used to prioritize people with type 2 diabetes for retinal screening to detect STDR. Design, setting, and participants: This c...
Article
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Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogene...
Article
Experimental Autoimmune Uveitis (EAU) is driven by immune cells responding to self-antigens. Many features of this non-infectious, intraocular inflammatory disease model recapitulate the clinical phenotype of posterior uveitis affecting humans. EAU has been used reliably to study the efficacy of novel inflammatory therapeutics, their mode of action...
Article
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Retinal 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 n...
Article
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Background During neuroinflammation many chemokines alter the function of the blood-brain barrier (BBB) that regulates the entry of macromolecules and immune cells into the brain. As the milieu of the brain is altered, biochemical and structural changes contribute to the pathogenesis of neuroinflammation and may impact on neurogenesis. The chemokin...
Article
Background A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tum...
Article
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Metastasis is the primary cause of cancer-related mortality. Tumor cell interactions with cells of the vessel wall are decisive and potentially rate-limiting for metastasis. The molecular nature of this cross-talk is, beyond candidate gene approaches, hitherto poorly understood. Using endothelial cell (EC) bulk and single-cell transcriptomics in co...
Article
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The neurovascular unit (NVU) is a complex multi-cellular structure consisting of endothelial cells (ECs), neurons, glia, smooth muscle cells (SMCs), and pericytes. Each component is closely linked to each other, establishing a structural and functional unit, regulating central nervous system (CNS) blood flow and energy metabolism as well as forming...
Article
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Leucine-rich a-2-glycoprotein 1 (LRG1) is a candidate therapeutic target for treating the neovascular form of age-related macular degeneration (nvAMD). In this study we examined the expression of LRG1 in eyes of nvAMD patients. Choroidal neovascular membranes (CNVMs) from patients who underwent submacular surgery for retinal pigment epithelium–chor...
Article
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Leucine-rich alpha-2-glycoprotein 1 (LRG1) is present abundantly in the microenvironment of many tumours where it contributes to vascular dysfunction, which impedes the delivery of therapeutics. In this work we demonstrate that LRG1 is predominantly a non-internalising protein. We report the development of a novel antibody–drug conjugate (ADC) comp...
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Importance Eyes with proliferative diabetic retinopathy have a variable response to treatment with panretinal photocoagulation (PRP) or anti–vascular endothelial growth factor agents. The location of neovascularization (NV) is associated with outcomes (eg, patients with disc NV [NVD] have poorer visual prognosis than those with NV elsewhere [NVE])....
Article
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Background The integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets. Methods Mice (female; B10...
Article
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Lymphocyte transendothelial migration (TEM) relies on ICAM-1 engagement on the luminal surface of the endothelial cells (ECs). In blood–brain barrier (BBB) ECs, ICAM-1 triggers TEM signalling, including through JNK MAP kinase and AMP-activated protein kinase (AMPK), which lead to the phosphorylation and internalisation of the adherens junction prot...
Preprint
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Vascular dysfunction contributes to the pro-oncogenic tumor microenvironment and impedes the delivery of therapeutics. Normalizing of the tumor vasculature has therefore become a potential therapeutic objective. We previously reported that the secreted glycoprotein, leucine-rich α-2-glycoprotein 1 (LRG1), contributes to the formation of pathogenic...
Article
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New clinical trials for diabetic macular oedema (DMO) are being designed to prove superiority over aflibercept when this agent is already very effective in improving visual acuity (VA) and DMO. The aim of this study was to determine the optimal inclusion–exclusion criteria for trials to aim for superiority in visual outcomes with newer agents. As P...
Article
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Delayed wound healing is commonly associated with diabetes. It may lead to amputation and death if not treated timely. Limited treatments are available partially due to the poor understanding of the complex disease pathophysiology. Here, we investigated the role of Leucine-rich alpha-2-glycoprotein1 (LRG1) in normal and diabetic wound healing. Firs...
Preprint
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Background: The integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets. Methods: Mice (female; B1...
Conference Paper
In cancer blood vessels are dysfunctional, poorly perfused and leaky. Malfunctioning vessels contribute to the pro-oncogenic environment and limit the efficacy of current systemically administered drugs. Normalizing the tumor vasculature to improve vessel permeability, reduce hypoxia and vascular leakage and enhance drug delivery, has become an exp...
Conference Paper
Although the use of checkpoint inhibitors and adoptive T cell therapy have been reported in multiple cancers resulting in a plethora of clinical trials, the efficacy of these therapeutic strategies is often limited by the presence of impaired vasculature in the tumour mass. Indeed, in solid tumors, blood vessels are dysfunctional, leaky and poorly...
Article
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Introduction The ORNATE India project is funded by the UK Research and Innovation (UKRI) through the Global Challenges Research Fund. The aim is to build research capacity and capability in India and the UK to tackle global burden of diabetes-related visual impairment. As there are over 77 million people with diabetes in India, it is challenging to...
Preprint
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Pathological angiogenesis contributes to morbidity in a number of diseases including cancer, diabetic retinopathy and the neovascular form of age-related macular degeneration, leading to significant efforts to develop effective anti-angiogenic therapeutics for these conditions. The field is dominated by inhibitors of vascular endothelial growth fac...
Article
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Purpose: The 32W and 32Q variants of complement factor B (CFB) are associated with reduced risk of developing neovascular age-related macular degeneration (AMD) compared with the common 32R allele. The objective of this study was to determine if the most protective R32Q variant affects the neovascular process in a manner consistent with the report...
Article
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The ORNATE India project is funded by the UK Research and Innovation (UKRI) through the Global Challenges Research Fund. The aim is to build research capacity and capability in India and the UK to tackle global burden of diabetes-related visual impairment. As there are over 77 million people with diabetes in India, it is challenging to screen every...
Article
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Wnt signalling mediates complex cell-cellinteractions during development and proliferation. Annexin A8 (AnxA8), a calcium-dependent phospholipid-binding protein, and canonical Wnt signalling mechanisms have both been implicated in retinal pigment epithelial (RPE) cell differentiation. The aim here was to examine the possibility of cross-talk betwee...
Conference Paper
Age-related macular degeneration (AMD) is a central vision-threatening disease, and its development is significantly associated with the Y402H variant in the complement factor H (Cfh) gene. Cfh is a soluble glycoprotein, and a negative regulator of complement activation. It is secreted by retinal pigment epithelium (RPE), liver and immune cells amo...
Article
Introduction: The purpose of this study was to generate a therapeutic function-blocking antibody against leucine-rich alpha-2-glycoprotein 1 (LRG1), a novel regulator of pathological angiogenesis that is up-regulated in many cancers, and demonstrate efficacy in proof of principle experiments in mouse models. Experimental Procedures: Mice were immun...
Article
Introduction: The aim of this study was to determine whether deletion of the gene coding for the secreted glycoprotein, leucine-rich alpha-2-glycoprotein 1 (LRG1), or blockade of its action through function-blocking antibody treatment, improves tumor vascular function. Experimental Procedures: The role of LRG1 was investigated in subcutaneous B16/F...
Article
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After publication of the article [1], it has been brought to our attention that there are some errors in the formatting of names in the final version of the article.
Article
The retinoic acid derivative fenretinide (FR) is capable of transdifferentiating cultured retinal pigment epithelial (RPE) cells towards a neuronal-like phenotype, but the underlying mechanisms are not understood. To identify genes involved in this process we performed a microarray analysis of RPE cells pre- and post-FR treatment, and observed a ma...
Article
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The retinal pigment epithelium (RPE) interacts closely with photoreceptors to maintain visual function. In degenerative diseases such as Stargardt disease and age-related macular degeneration, the leading cause of blindness in the developed world, RPE cell loss is followed by photoreceptor cell death. RPE cells can proliferate under certain conditi...
Article
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This is a report on the CNS barrier congress held in London, UK, March 22–23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the bra...
Article
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Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activate...
Article
Purpose In diseases characterized by abnormal neovascularization, the new vessels lack adequate pericyte (PC) coverage. TGFβ is involved in the recruitment of PC through ALK1-Smad1/5/8 and ALK5-Smad2/3 signalling. The first signalling pathway inhibits differentiation into mural cells while the latter promotes it. Leucine-rich α-2-glycoprotein 1 (LR...
Article
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The purpose of this study was to examine the retinas of mice carrying hemizygous and null double deletions of Cfb-/- and Cfh-/-, and to compare these with the single knockouts of Cfb, Cfh and Cfd. Retinas were isolated from wild type (WT), Cfb-/-/Cfh-/-, Cfb-/-/Cfh+/-, Cfh-/-/Cfb+/-, Cfb-/-, Cfh-/- Cfd-/-, and Cfd+/- mice. Complement proteins were...
Article
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Background/aims: We examined the effect of human complement sera (HCS) on retinal pigment epithelial (RPE) cells with respect to pro-inflammatory mediators relevant in early age-related macular degeneration (AMD). Methods: RPE cells were treated with complement-containing HCS or with heat-inactivated (HI) HCS or C7-deficient HCS as controls. Cel...
Article
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The mouse fetal metatarsal provides a unique tool for studying angiogenesis. In comparison with other commonly used in vitro or ex vivo angiogenesis assays, vessel outgrowth from mouse fetal metatarsals is more representative of sprouting angiogensis in vivo. It allows the analysis of blood vessel growth, and the mechanisms underpinning this proces...
Conference Paper
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Background The retinoic acid derivative Fenretinide (Fr) is capable of trans-differentiating retinal pigment epithelial (RPE) cells towards a neuron-like phenotype in culture. Microarray analysis of Fr-treated ARPE-19 cells revealed down-regulation of annexin (anx) A8 in trans-differentiated cells. AnxA8, a calcium-dependent phospholipid-binding pr...
Article
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Retinal pigment epithelial (RPE) cell death is a hallmark of age-related macular degeneration. The alternative pathway of complement activation is strongly implicated in RPE cell dysfunction and loss in age-related macular degeneration; therefore, it is critical that RPE cells use molecular strategies to mitigate the potentially harmful effects of...
Article
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Abnormal angiogenesis is associated with many blinding eye diseases. Targeting VEGF, a master regulator of blood vessel formation, has shown improved outcomes in ocular vascular disorders. However, many patients do not respond or respond poorly to anti-VEGF therapy, which is not surprising as angiogenesis is regulated by a delicate balance of diver...
Article
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The vascular endothelium operates in a highly polarized environment, but to date there has been little exploration of apicobasal polarization of its signaling. We show that VEGF-A, histamine, IGFBP3, and LPA trigger unequal endothelial responses when acting from the circulation or the parenchymal side at blood-neural barriers. For VEGF-A, highly po...
Article
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Immune cell trafficking requires the frequent breaching of the endothelial barrier either directly through individual cells (a 'transcellular' route) or through the inter-endothelial junctions (a 'paracellular' route). What determines the loci/route of breaching events is an open question with important implications for overall barrier regulation....
Conference Paper
Purpose. Fenretinide (FR), a retinoic acid derivative, is capable of trans-differentiating retinal pigment epithelial (RPE) cells into a neuronal-like phenotype in culture. Microarray analysis pre- and post-FR treatment revealed down-regulation of Annexin (Anx) A8 and various proteins involved in Wnt signalling in trans-differentiated cells. AnxA8,...