MCP-1 Deficiency Delays Regression of Pathologic Retinal Neovascularization in a Model of Ischemic Retinopathy

Davies, M.; Stempel, Andrew J.; Powers, Michael R.

doi:10.1167/iovs.07-1491

Cited by 42 publications

(37 citation statements)

References 56 publications

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“…Interestingly, some of these macrophages were observed in vivo with pseudopodia-like extensions connecting to vascular endothelial cells over a distance. These findings are in accordance with earlier reports of macrophages associated with cells that are dying or are destined to be removed from a regressing tissue [1,2,5,7,10]. Ausprunk et al additionally suspected a similar monocyte-to-macrophage transition of cells in close proximity to walls of regressing capillaries [10].…”

Section: In Vivo Imaging Of Human Corneal Capillary Regression: Reporsupporting

confidence: 91%

“…This is in contrast to our earlier findings of CD11b+ myeloid cells extravasating from limbal vessels to infiltrate the corneal stroma shortly after induction of inflammation, with an increasing number of mature macrophages accumulating in the stroma during the pro-angiogenic phase [33]. Our model could be used in the future to investigate the emergence of various macrophage subtypes as the angiogenic balance changes from a pro-to anti-angiogenic environment [5,7].…”

Section: In Vivo Imaging Of Human Corneal Capillary Regression: Reporcontrasting

confidence: 69%

“…endothelium and removal of vascular debris by macrophages. Macrophages have also been shown to play a key role in other non-inflammatory models of capillary regression [1,2,[5][6][7] by initiating degradation of vascular endothelium. Although vascular endothelium is believed to be digested by macrophages, remnants of basement membrane from regressing capillaries have been shown to persist, constituting so-called 'string' or 'ghost' vessels in various tissues [10,14].…”

Section: Introductionmentioning

confidence: 99%

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Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model

2011

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Abstract:In this study, we introduce a technique for repeated, microscopic observation of single regressing capillaries in vivo in inflamed murine corneas. Natural capillary regression was initiated by removal of inflammatory stimulus during an active pro-angiogenic phase, while the additional impact of anti-angiogenic treatment with triamcinolone or bevazicumab was investigated. Capillaries regressed naturally within one week and treatments did not further enhance the natural regression. Morphologically, early-phase regression was characterized by significant lumen narrowing and a significant reduction in CD11b+ myeloid cell infiltration of the extracellular matrix. By one week, vascular remodeling occurred concomitant with CD11b+CD68+KiM2R+ mature macrophage localization on capillary walls. Empty conduits without blood flow, positive for collagen IV and devoid of vascular endothelium and pericytes, were apparent in vivo and by three weeks were more numerous than perfused capillaries. By three weeks, macrophages aggregated around remaining perfused capillaries and were observed in apposition with degrading capillary segments. Abrupt termination of capillary sprouting in our regression model further revealed vascular endothelial abandonment of sprout tips and perfused capillary loop formation within a single angiogenic sprout, possibly as an intussusceptive response to cessation of the stimulus. Finally, we observed lumen constriction and macrophage localization on capillary walls in vivo in a clinical case of corneal capillary regression that paralleled findings in our murine model.

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Section: In Vivo Imaging Of Human Corneal Capillary Regression: Reporsupporting

confidence: 91%

Section: In Vivo Imaging Of Human Corneal Capillary Regression: Reporcontrasting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model

2011

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“…34 Other members of the chemokine family, such as MCP-1 and SDF-1/CXCR4, have been reported to regulate BM-MLC trafficking in hypoxic retinas and the subsequent pathological NV. 15,35 However, the relationship between the diverse hypoxia-induced chemokines, trafficking properties of the BM-MLCs, and the variety of biological functions in hypoxic retinas are not fully understood. It is also known that VEGF contributes to the recruitment of monocytes to hypoxic tissues.…”

Section: Discussionmentioning

confidence: 99%

“…These cells might have an antiangiogenic role, which is supported by an earlier report, showing the involvement of macrophages/microglia in pathological NV regression through apoptosis. 35 The current therapeutic approaches for ocular neovascular diseases mainly focus on inhibiting the pathological NV with antiangiogenic compounds such as VEGF inhibitors and angiostatic steroids. In addition, laser photocoagulation of hypoxic retinal tissue with the idea of causing the regression of pathological NV, as the ischemic drive is decreased, is also being used.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow-derived monocyte lineage cells recruited by MIP-1β promote physiological revascularization in mouse model of oxygen-induced retinopathy

Ishikawa

Nakao

Sassa

et al. 2012

Laboratory Investigation

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Recent clinical observations have indicated that vascular endothelial growth factor (VEGF) is a key factor that stimulates the development of preretinal pathological neovascularization (NV). However, it has not been established how intraretinal physiological revascularization of hypoxic avascular areas is regulated. Our earlier study on the gene expression profile of hypoxic retinas in a mouse model of oxygen-induced retinopathy (OIR) showed that macrophage inflammatory protein-1b (MIP-1b) was the most upregulated protein. The purpose of this study was to investigate the role played by MIP-1b in recruiting bone marrow-derived monocyte lineage cells (BM-MLCs) in a mouse model of OIR. Our results showed that MIP-1b was upregulated, and its receptor, CCR5, was expressed in BM-MLCs in the hypoxic inner retina. Neutralizing Ab against MIP-1b reduced the infiltration of BM-MLCs into the OIR retinas and increased the avascular area and preretinal neovascular tufts. A very strong significant correlation was found between the area of the preretinal neovascular tufts and the avascular area, regardless of the extent of BM-MLC infiltration into the OIR retinas. Additional treatment with VEGF-A-neutralizing Ab showed that the MIP-1b-regulated pathological NV strongly depended on VEGF-A, which was probably secreted by the hypoxic avascular retinas. These results indicate that MIP-1b is involved in the recruitment of BM-MLCs, which have a significant role in the physiological revascularization of hypoxic avascular retinas. Overall, these findings indicate that the MIP-1b induction of BM-MLCs might possibly be used to promote intraretinal revascularization and thus prevent the abnormal NV in ischemic vision-threatening retinal diseases. Tissue hypoxia is believed to be the common mechanism that initiates a series of events leading to compensatory angiogenesis. Hypoxia-induced retinal neovascularization (NV) is the main contributor to proliferative vascular diseases, such as diabetic retinopathy, retinopathy of prematurity, and retinal vein occlusion. These diseases can lead to irreversible damage to visual function.To determine the factors that are activated during retinal hypoxia, we performed a gene expression profile of hypoxic retinas obtained from a mouse model of oxygen-induced retinopathy (OIR) using gene microarray analyses. The results identified the functional set of genes that are related to the post-ischemic inflammation, neural and vascular development, and subsequent pathological NV. The most upregulated gene among the differentially expressed genes in hypoxic retinas was the macrophage inflammatory protein1b (MIP-1b) and not vascular endothelial growth factor A (VEGF-A) and other chemokines. 1 MIP-1b, also known as chemokine CC motif ligand 4, is a member of the CC chemokine family that are characterized by their ability to direct migration of leukocytes into inflamed tissues. 2 MIP-1b was first isolated from the culture medium of LPS-activated macrophages, 3 and it recruited macrophages/microglia to the sites of...

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Complement Involvement in Neovascular Ocular Diseases

Yanai

Connor

2011

Advances in Experimental Medicine and Biology

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Angiogenesis underlies the majority of eye diseases that result in catastrophic loss of vision. Recent evidence has implicated the integrins r4P3 and Cv435 in the angiogenic process. We examined the expression of C4133 and CX485 in neovascular ocular tissue from patients with subreti-nal neovascularization from age-related macular degenera-tion or the presumed ocular histoplasmosis syndrome or retinal neovascularization from proliferative diabetic retinop-athy (PDR). Only rv13 was observed on blood vessels in ocular tissues with active neovascularization from patients with age-related macular degeneration or presumed ocular his-toplasmosis, whereas both aP3 and aP5 were present on vascular cells in tissues from patients with PDR Since we observed both integrins on vascular cells from tissues of patients with retinal neovascularization from PDR, we examined the effects of a systemically administered cyclic peptide antagonist of aM83 and C4185 on retinal angiogenesis in a murine model. This antagonist specifically blocked new blood vessel formation with no effect on established vessels. These results not only reinforce the concept that retinal and sub-retinal neovascular diseases are distinct pathological processes , but that antagonists of a433 and/or aC45 may be effective in treating individuals with blinding eye disease associated with angiogenesis. The pathological growth of new blood vessels underlies most eye diseases that cause catastrophic loss of vision. The leading cause of blindness in individuals over the age of 55 is age-related macular degeneration (ARMD); under 55 years of age, the leading cause is proliferative diabetic retinopathy (PDR) (1). The two diseases are further distinguished by the specific site of new blood vessel growth; ARMD is characterized by choroidal neovascularization (2), whereas in PDR retinal blood vessels proliferate along the surface of the retina and into the posterior vitreous (3). [The posterior eye has a dual blood supply consisting of (i) the retinal blood vessels that branch from the central retinal artery and supply the inner one-third of the retina and (ii) the choroid that forms an extensive subretinal vascular plexus and nourishes the outer two-thirds of the retina.] While ARMD and PDR are proto-typic diseases for choroidal and retinal neovascularization, respectively, other conditions can selectively cause angiogen-esis of either vasculature. In general, diseases of a degenerative (e.g., ARMD, pathological myopia) or inflammatory [e.g., presumed ocular histoplasmosis syndrome (POHS)] nature manifest as choroidal neovascularization, whereas ischemic diseases (e.g., PDR, retinopathy of prematurity, sickle cell retinopathy) result in retinal angiogenesis. Although a number of recent studies have demonstrated an association between elevated intraocular levels of vascular endothelial growth factor (VEGF) and ischemia-related retinal neovasculariza-tion (4-6), very little is known about the mechanism underlying vasoproliferation in these neovascular eye diseases.

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MCP-1 Deficiency Delays Regression of Pathologic Retinal Neovascularization in a Model of Ischemic Retinopathy

Cited by 42 publications

References 56 publications

Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model

Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model

Bone marrow-derived monocyte lineage cells recruited by MIP-1β promote physiological revascularization in mouse model of oxygen-induced retinopathy

Complement Involvement in Neovascular Ocular Diseases

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