Cursiefen, C. et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc. Natl. Acad. Sci. USA 103 , 11405-11410

Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2006; 103(30):11405-10. DOI: 10.1073/pnas.0506112103
Source: PubMed


Transparency of the cornea, the window of the eye, is a prerequisite for vision. Angiogenesis into the normally avascular cornea is incompatible with good vision and, therefore, the cornea is one of the few tissues in the human body where avascularity is actively maintained. Here, we provide evidence for a critical mechanism contributing to corneal avascularity. VEGF receptor 3, normally present on lymphatic and proliferating blood vascular endothelium, is strongly constitutively expressed by corneal epithelium and is mechanistically responsible for suppressing inflammatory corneal angiogenesis.

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    • "The corneal epithelium constitutively expresses VEGFR-3, which binds to angiogenic VEGF-C and VEGF-D. As a result, it inhibits both hemangiogenesis and lymphangiogenesis, thereby contributing to the regulation of ocular surface immunity (Cursiefen et al., 2006). Another important anti-angiogenic factor constitutively expressed by cornea is thrombospondin (TSP)-1 (Hiscott et al., 1997), which helps to suppress inflammation-induced corneal angiogenesis (Cursiefen et al., 2004; Cursiefen et al., 2011). "
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    ABSTRACT: The tear film, lacrimal glands, corneal and conjunctival epithelia and Meibomian glands work together as a lacrimal functional unit (LFU) to preserve the integrity and function of the ocular surface. The integrity of this unit is necessary for the health and normal function of the eye and visual system. Nervous connections and systemic hormones are well known factors that maintain the homeostasis of the ocular surface. They control the response to internal and external stimuli. Our and others' studies show that immunological mechanisms also play a pivotal role in regulating the ocular surface environment. Our studies demonstrate how anti-inflammatory factors such as the expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in corneal cells, immature corneal resident antigen-presenting cells, and regulatory T cells play an active role in protecting the ocular surface. Dry eye disease (DED) affects millions of people worldwide and negatively influences the quality of life for patients. In its most severe forms, DED may lead to blindness. The etiology and pathogenesis of DED remain largely unclear. Nonetheless, in this review we summarize the role of the disruption of afferent and efferent immunoregulatory mechanisms that are responsible for the chronicity of the disease, its symptoms, and its clinical signs. We illustrate current anti-inflammatory treatments for DED and propose that prevention of the disruption of immunoregulatory mechanisms may represent a promising therapeutic strategy towards controlling ocular surface inflammation.
    Progress in Retinal and Eye Research 03/2012; 31(3):271-85. DOI:10.1016/j.preteyeres.2012.02.003 · 8.73 Impact Factor
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    • "Upregulation of matrix-derived anti-angiogenic factors such as endostatin (Kato et al., 2003) and restin (Saika et al., 2004), along with increased anti-inflammatory factor IL-1ra may play an important role in LSC and AM transplantation-mediated anti-angiogenic effect. Recently, Cursiefen et al. demonstrated a critical mechanism that contributed to corneal avascularity by VEGF receptor 3, which is normally present on lymphatic and proliferating blood vascular endothelium, is strongly constitutively expressed by corneal epithelium and is mechanistically responsible for suppressing inflammatory corneal angiogenesis (Cursiefen et al., 2006). Knowledge gained from using epithelia–matrix interaction to regulate corneal angiogenesis will enable us to optimize the anti-angiogenic effect of the cultivated cells like oral mucosal epithelial cells or mesehchymal stem cells for future ocular surface reconstruction. "

    New Advances in Stem Cell Transplantation, 02/2012; , ISBN: 978-953-51-0013-3
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    • "The cornea of the eye is a physiologically transparent and avascular tissue [8], consisting out of densely packed collagen fibrils with almost no scattering properties. This tissue is perfectly suitable for microscopic investigations and also easily accessible in the living animal. "
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    ABSTRACT: The role of lymphatic vessels in tissue and organ transplantation as well as in tumor growth and metastasis has drawn great attention in recent years. We now developed a novel method using non-invasive two-photon microscopy to simultaneously visualize and track specifically stained lymphatic vessels and autofluorescent adjacent tissues such as collagen fibrils, blood vessels and immune cells in the mouse model of corneal neovascularization in vivo. The mouse cornea serves as an ideal tissue for this technique due to its easy accessibility and its inducible and modifiable state of pathological hem- and lymphvascularization. Neovascularization was induced by suture placement in corneas of Balb/C mice. Two weeks after treatment, lymphatic vessels were stained intravital by intrastromal injection of a fluorescently labeled LYVE-1 antibody and the corneas were evaluated in vivo by two-photon microscopy (TPM). Intravital TPM was performed at 710 nm and 826 nm excitation wavelengths to detect immunofluorescence and tissue autofluorescence using a custom made animal holder. Corneas were then harvested, fixed and analyzed by histology. Time lapse imaging demonstrated the first in vivo evidence of immune cell migration into lymphatic vessels and luminal transport of individual cells. Cells immigrated within 1-5.5 min into the vessel lumen. Mean velocities of intrastromal corneal immune cells were around 9 µm/min and therefore comparable to those of T-cells and macrophages in other mucosal surfaces. To our knowledge we here demonstrate for the first time the intravital real-time transmigration of immune cells into lymphatic vessels. Overall this study demonstrates the valuable use of intravital autofluorescence two-photon microscopy in the model of suture-induced corneal vascularizations to study interactions of immune and subsequently tumor cells with lymphatic vessels under close as possible physiological conditions.
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