Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands

Chung, Eun‐Sung; Chauhan, Sunil; Jin, Yiping; Nakao, Shintaro; Hafezi-Moghadam, Ali; Rooijen, Nico van; Zhang, Qiang; Chen, Lu; Dana, Reza

doi:10.2353/ajpath.2009.080515

Cited by 84 publications

(68 citation statements)

References 43 publications

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“…35,49,50 Previous reports have shown that systemic or local macrophage depletion inhibited pathological neovascularization in several ocular models. 33,34,[51][52][53] In our study, the majority of TLR4-and HMGB1-positive cells were F4/80 positive cells in the injured corneas. Moreover, in vitro, the main HMGB1-induced angiogenic factor from murine peritoneal macrophages of WT mice but not of TLR4 Ϫ/Ϫ mice was VEGF.…”

Section: Discussionsupporting

confidence: 54%

High-Mobility Group Box-1 Mediates Toll-Like Receptor 4–Dependent Angiogenesis

Lin

Yang

Fang

et al. 2011

ATVB

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Objective-Inflammation is closely linked to angiogenesis, and Toll-like receptors (TLRs) are the key mediators of inflammatory responses. However, the impact of TLRs on angiogenesis is incompletely understood. In this study, we determined the involvement of TLRs in angiogenesis. Methods and Results-In a mouse model of alkali-induced corneal neovascularization (CNV), we found that CNV was attenuated in TLR4 Ϫ/Ϫ but not TLR2 Ϫ/Ϫ mice. Further study revealed that the absence of TLR4 led to decreased production of proangiogenic factors in association with reduced accumulation of macrophages at the site of wounds, which was associated with reduced expression of high-mobility group box-1 (HMGB1) protein, an endogenous ligand for TLR4. Topical application of HMGB1 to the injured cornea promoted CNV with increased macrophage accumulation in wild-type mice but not in TLR4 Ϫ/Ϫ mice. HMGB1 treatment in vitro also promoted the production of proangiogenic factors by mouse macrophages in a TLR4-dependent manner. Furthermore, antagonists of HMGB1 and TLR4 reduced CNV and macrophage recruitment in the injured cornea of wild-type mice. Conclusion-Our

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Section: Discussionsupporting

confidence: 54%

High-Mobility Group Box-1 Mediates Toll-Like Receptor 4–Dependent Angiogenesis

Lin

Yang

Fang

et al. 2011

ATVB

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“…To approach this, we compared the number of macrophages in infant and adult corneas 1 week after suture placement using the standard protocol as described previously. 22,26,27 Our results from this assay revealed that the number of macrophages was significantly higher in infant than in adult corneas, as shown in Figure 5 (*P < 0.05).…”

Section: Infant Cornea Exhibits Enhanced Macrophage Infiltrationmentioning

confidence: 60%

“…Macrophage infiltration was also evaluated according to the standard protocol. 22,26,27 Briefly, total 10 areas (8 from the periphery and 2 from the center) of each sample were randomly picked and examined under the epifluorescence microscope. Total numbers of F4/80 positive cells were counted throughout the whole thickness of the picked area.…”

Section: Vascular and Macrophage Quantificationmentioning

confidence: 99%

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Increased Lymphangiogenesis and Hemangiogenesis in Infant Cornea

Yuen

Leu

Sadovnikova

et al. 2011

Lymphatic Research and Biology

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Background: Corneal lymphangiogenesis (LG) and hemangiogenesis (HG) accompany many diseases after inflammatory, infectious, traumatic or chemical insults. They also contribute to transplant rejection. It is known that corneal transplants in infants or children have a higher rejection rate than in adults. However, it has never been studied whether infant corneas differ from adult corneas in inflammatory LG, HG, or both, which is the focus of this study. Methods and Results: Corneal inflammatory LG and HG were induced by a standard suture placement model in C57BL/6 mice of 3 weeks and 8 weeks of age, respectively. Corneal LG, HG, and macrophage infiltration were assessed by immunofluorescent microscopic studies using specific antibodies against CD31 (a panendothelial cell marker), LYVE-1 (a lymphatic marker), and F4/80 (a macrophage marker). Blood vessels were also examined by ophthalmic slit-lamp microscopic assays in vivo. Digital images were analyzed by NIH Image J software. It was found, for the first time, that infant corneas exhibited a higher level of LG, HG, and macrophage infiltration during inflammation. Infant lymphatic and blood vessels demonstrated greater density and invasion area but similar branching points. Additionally, infant lymphatic vessels were also of larger diameter. Conclusions: Infant and adult corneas differ greatly in their inflammatory responses of LG, HG, and macrophage infiltration. These novel findings will shed some light on our understanding of the LG and HG processes, as well as the development of new therapeutic protocols for corneal diseases, particularly, in infants or children, where an early restoration of sight is critically important in preventing amblyopia or permanent vision loss.

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“…and upregulation or trends towards upregulation of Flt4, which participates in the recruitment of VEGF-A-secreting macrophages involved in angiogenesis [48], F3 and Mmp19 [49,50].…”

Section: Attempts To Compensate Perinatal Deleterious Effects In Islementioning

confidence: 99%

Hypercholesterolaemia, signs of islet microangiopathy and altered angiogenesis precede onset of type 2 diabetes in the Goto–Kakizaki (GK) rat

Lacraz

et al. 2011

Diabetologia

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Aims/hypothesis The adult non-obese Goto-Kakizaki (GK) rat model of type 2 diabetes, particularly females, carries in addition to hyperglycaemia a genetic predisposition towards dyslipidaemia, including hypercholesterolaemia. As cholesterol-induced atherosclerosis may be programmed in utero, we looked for signs of perinatal lipid alterations and islet microangiopathy. We hypothesise that such alterations contribute towards defective pancreas/islet vascularisation that might, in turn, lead to decreased beta cell mass. Accordingly, we also evaluated islet inflammation and endothelial activation in both prediabetic and diabetic animals.Methods Blood, liver and pancreas were collected from embryonic day (E)21 fetuses, 7 dayold prediabetic neonates and 2.5 month-old diabetic GK rats and Wistar controls for analysis/quantification of: (1) Results Systemic and hepatic cholesterol anomalies already exist in GK fetuses and neonates.Hyperglycaemic GK fetuses exhibit a similar percentage decrease in total pancreas and islet vascularisation and beta cell mass. Normoglycaemic GK neonates show systemic inflammation, signs of islet pre-microangiopathy, disturbed angiogenesis, collapsed vascularisation and altered pancreas development. Concomitantly, GK neonates exhibit elevated defence mechanisms.Conclusions/interpretation These data suggest an autoinflammatory disease, triggered by in utero programming of cholesterol-induced islet microangiopathy interacting with chronic hyperglycaemia in GK rats. During the perinatal period, GK rats show also a marked deficient islet vascularisation in conjunction with decreased beta cell mass.

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Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands

Cited by 84 publications

References 43 publications

High-Mobility Group Box-1 Mediates Toll-Like Receptor 4–Dependent Angiogenesis

High-Mobility Group Box-1 Mediates Toll-Like Receptor 4–Dependent Angiogenesis

Increased Lymphangiogenesis and Hemangiogenesis in Infant Cornea

Hypercholesterolaemia, signs of islet microangiopathy and altered angiogenesis precede onset of type 2 diabetes in the Goto–Kakizaki (GK) rat

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