TRAIL-Deficient Mice Exhibit Delayed Regression of Retinal Neovascularization

Hubert, K. E.; Davies, M.; Stempel, Andrew J.; Griffith, Thomas S.; Powers, Michael R.

doi:10.2353/ajpath.2009.090099

Cited by 17 publications

(20 citation statements)

References 50 publications

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“…Other studies showed that apoptotic bodies derived from neovessel mediate release of cytokines and chemokines that facilitate progenitor cell recruitment, further supporting a role for TNF-␣ in vascular tuft regression (60). Additionally, CCN1 enhances the apoptotic activity of TRAIL and Fas ligand, which has been shown to be involved in endothelial cell death associated with vascular tuft regression (61). Thus, CCN1 induces a selective modulation of TNF-␣ activity that may translate into a more efficient and rapid vascular recovery.…”

Section: Discussionmentioning

confidence: 88%

The Matricellular Protein Cysteine-rich Protein 61 (CCN1/Cyr61) Enhances Physiological Adaptation of Retinal Vessels and Reduces Pathological Neovascularization Associated with Ischemic Retinopathy

Hasan

Pokeza

Shaw

et al. 2011

Journal of Biological Chemistry

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Retinal vascular damages are the cardinal hallmarks of retinopathy of prematurity (ROP), a leading cause of vision impairment and blindness in childhood. Both angiogenesis and vasculogenesis are disrupted in the hyperoxia-induced vaso-obliteration phase, and recapitulated, although aberrantly, in the subsequent ischemia-induced neovessel formation phase of ROP. Yet, whereas the histopathological features of ROP are well characterized, many key modulators with a therapeutic potential remain unknown. The CCN1 protein also known as cysteine-rich protein 61 (Cyr61) is a dynamically expressed, matricellular protein required for proper angiogenesis and vasculogenesis during development. The expression of CCN1 becomes abnormally reduced during the hyperoxic and ischemic phases of ROP modeled in the mouse eye with oxygen-induced retinopathy (OIR). Lentivirus-mediated re-expression of CCN1 enhanced physiological adaptation of the retinal vasculature to hyperoxia and reduced pathological angiogenesis following ischemia. Remarkably, injection into the vitreous of OIR mice of hematopoietic stem cells (HSCs) engineered to express CCN1 harnessed ischemiainduced neovessel outgrowth without adversely affecting the physiological adaptation of retinal vessels to hyperoxia. In vitro exposure of HSCs to recombinant CCN1 induced integrin-dependent cell adhesion, migration, and expression of specific endothelial cell markers as well as many components of the Wnt signaling pathway including Wnt ligands, their receptors, inhibitors, and downstream targets. CCN1-induced Wnt signaling mediated, at least in part, adhesion and endothelial differentiation of cultured HSCs, and inhibition of Wnt signaling interfered with normalization of the retinal vasculature induced by CCN1-primed HSCs in OIR mice. These newly identified functions of CCN1 suggest its possible therapeutic utility in ischemic retinopathy.Retinopathy of prematurity (ROP), 2 a leading cause of visual impairment in low birth weight infants, is initiated by delayed retinal vascular growth and insufficient vascularization after premature birth (1). A disrupted oxygen environment in the retina of severely premature neonates is a key factor in the onset of retinal vaso-obliteration and the development of ROP. Retinal ischemia is the underlying cause triggering the release of angiogenic factors that promote the formation of aberrant vessels, which then break through the inner limiting membrane into the vitreous causing vitreous hemorrhage, tractional retinal detachment, and vision loss.The normal retinal vasculature, which is planar in nature, is well organized into three capillary plexuses generated during retinal development in a well coordinated manner. Conversely, pathological neovascularization generates disorganized, leaky, and tortuous vessels prone to exudation, hemorrhage, and fibrosis that damage the retina ultimately causing blindness. The collective work of many investigators has resulted in a greater appreciation of the pathogenic factors involved (2-5). The balance be...

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Section: Discussionmentioning

confidence: 88%

The Matricellular Protein Cysteine-rich Protein 61 (CCN1/Cyr61) Enhances Physiological Adaptation of Retinal Vessels and Reduces Pathological Neovascularization Associated with Ischemic Retinopathy

Hasan

Pokeza

Shaw

et al. 2011

Journal of Biological Chemistry

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“…BCL2L11 expression was responsible for the inherent sensitivity of the developing retinal vasculature to changes in oxygen levels and promoted vessel obliteration in response to hyperoxia [42] . TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), another important proapoptotic factor, is also vital for retinal vasoobliteration and subsequent neovascularization in the mouse OIR model [43] . It has been suggested that no expression of TRAIL in the retina was beneficial for the prevention of retinal neovascularization.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-126 Reduces Blood-Retina Barrier Breakdown via the Regulation of VCAM-1 and BCL2L11 in Ischemic Retinopathy

Bai¹,

Luo²,

Zhang

et al. 2017

Ophthalmic Res

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To evaluate the role of microRNA-126 (miR-126) in maintaining the integrity of the blood-retina barrier (BRB), we established a mouse model of oxygen-induced retinopathy (OIR) and measured the retinal levels of miR-126 using recombinant plasmid pCMV-MIR or pCMV-MIR-126 intravitreal injections. We also detected VCAM-1 and BCL2L11 levels. Retinal vaso-obliteration, VCAM-1 localization on retinal endothelial cells, the blood-retina vascular permeability or albumin leakage in retinas, TUNEL histology, Evans blue assays, or Western blotting for detecting albumin or tight junction levels in the retina was performed. We also detected the effect of miR-126 on the survival of Müller cells in a mouse model using vimentin fluorescence staining. Our results suggested that miR-126 may not only regulate the overexpression of VCAM-1 or BCL2L11 and lead to the reduction of retinal endothelial cell apoptosis, retinal vascular leakage, or retinal permeability in the OIR mouse model, but may also protect hypoxic retinal Müller cells via the STAT3 signaling pathway. We believe that miR-126 could also be a potential therapeutic agent to maintain the stability of the BRB in ischemic retinopathy.

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“…TRAIL expression in the eye is restricted to sites of interaction between key internal ocular structures and the surrounding tissue, much like that for Fas ligand (Griffith et al, 1995; Stuart et al, 1997). TRAIL expression in the retina is also an important regulator of oxygen-induced retinopathy (Hubert et al, 2009). Examination of the placenta, another immune privileged site, found TRAIL expression in syncytiotrophoblasts and Hofbauer cells, as well as a few other placental cell types (Phillips et al, 1999).…”

Section: Immunotherapy Involving Trail Receptor Agonists In Non-camentioning

confidence: 99%

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

Amarante-Mendes

Griffith

2015

Pharmacology & Therapeutics

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TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings — ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future.

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TRAIL-Deficient Mice Exhibit Delayed Regression of Retinal Neovascularization

Cited by 17 publications

References 50 publications

The Matricellular Protein Cysteine-rich Protein 61 (CCN1/Cyr61) Enhances Physiological Adaptation of Retinal Vessels and Reduces Pathological Neovascularization Associated with Ischemic Retinopathy

The Matricellular Protein Cysteine-rich Protein 61 (CCN1/Cyr61) Enhances Physiological Adaptation of Retinal Vessels and Reduces Pathological Neovascularization Associated with Ischemic Retinopathy

MicroRNA-126 Reduces Blood-Retina Barrier Breakdown via the Regulation of VCAM-1 and BCL2L11 in Ischemic Retinopathy

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

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