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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Available from: Pedram Hamrah
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    • "This pro-inflammatory action, in combination with the decline of the putative stem cell phenotype within the limbal epithelial population may cause an indirect pro(lymph)angiogenic shift in the limbus as a result of UVB exposure (Fig.7). Via recruitment of macrophages , hem-and lymphangiogenesis can be significantly upregulated (Cursiefen et al., 2006;Bock et al., 2013). Long term UVB exposure could therefore contribute to inflammation and pathologic neovascularization both consistent with the progression and recurrence of pterygium. "
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    ABSTRACT: Ultraviolet light B (UVB)-irradiation is linked to various ocular pathologies such as limbal stem cell defects in pterygium. Despite the large circumstantial evidence linking UVB irradiation and limbal epithelial stem cell damage, the precise molecular responses of limbal stem cells to UVB irradiation are unclear. Here the effect of UVB irradiation on the putative stem cell phenotype, limbal niche cells and the subsequent effects on corneal (lymph)angiogenic privilege were investigated. Primary human limbal epithelial stem cells and fibroblasts were irradiated with 0.02J/cm(2) of UVB, a low dose corresponding to 3min of solar irradiation. UVB irradiation caused significant reduction of limbal epithelial and limbal fibroblast proliferation for 24h, but apoptosis of limbal epithelial stem cells only. Moreover, UVB induced stem-like character loss of limbal epithelial cells, as their colony forming efficiency and putative stem cell marker expression significantly decreased. Interestingly, limbal epithelial cells co-cultured with UVB-irradiated limbal fibroblasts also exhibited loss of stem cell character and decrease of colony forming efficiency. Conditioned media from limbal epithelial cells inhibited lymphatic endothelial cell proliferation and tube network complexity; however this effect diminished following UVB irradiation. In contrast, pro-inflammatory and macrophage-recruiting cytokines such as TNFα, IFNγ and MCP1 were significantly upregulated following cell irradiation of limbal fibroblasts. These data demonstrate the key role of the limbal stem cell niche in response to UVB and subsequent (lymph)angiogenic and inflammatory events. These data suggest that the known pro(lymph)angiogenic effect of UVB irradiation in pterygium is not linked to a direct up-regulation of pro-angiogenic cytokines, but rather to indirect macrophage-recruiting cytokines being upregulated after UVB irradiation.
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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.
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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. "

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