Ambati, B.K. et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 443, 993-997

University of Aberdeen, Aberdeen, Scotland, United Kingdom
Nature (Impact Factor: 41.46). 11/2006; 443(7114):993-7. DOI: 10.1038/nature05249
Source: PubMed


Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.

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    • "Flt-1 receptor exists also as alternative spliced soluble form (sFlt-1) that represents one of the most potent physiological inhibitor of VEGFs activity (Kendall & Kenneth 1993). It is expressed during embryonic development where regulate the availability of VEGF and, as recently demonstrated, it is crucial to maintain the cornea in an avascular condition (Ambati et al. 2006). Many previous studies have proved the antiangiogenic activity of medicinal plants extracts or their secondary metabolites by inhibiting the interaction of both PlGF and VEGF-A with Flt-1 receptor (Ponticelli et al. 2008; Lepore et al. 2011; Tarallo et al. 2011; Pesca et al. 2013). "
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    ABSTRACT: Angiogenesis is involved in many physiological and pathological conditions. Natural compounds with antioxidant activity have also been reported to possess potent antiangiogenic properties by regulating angiogenesis modulators such as vascular endothelial growth factor (VEGF). Based on this, we screened the antioxidant and antiangiogenic activities of Astronium graveolens leaf extracts by a DPPH test and a competitive enzyme-linked immunosorbent assay, respectively. MeOH extract expressed a significant free radical-scavenging activity (EC50 = 37.65 μg/mL) and it was able to inhibit the interaction between placental growth factor (PlGF) (placental growth factor), a VEGF family member, and its receptor Flt-1 by more than 50% at 1 mg/mL. 1,2,3,4,6-Penta-O-galloyl-d-glucopyranose, 6 is the most active compound of the extract. It exhibited a high potency in scavenging DPPH (EC50 = 2.16 μg/mL) and reduced by 58% the PlGF/Flt-1 interaction at a concentration of 50 μM. Moreover, the known compounds (1-6) have been isolated for the first time in A. graveolens.
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    • "Furthermore, sFlt-1 is expressed in lens epithelial cells as well as pigment epithelial and photoreceptor cells in the eye, where it plays a role in maintaining avascularity in the cornea and in tissues outside of the retina (Ambati et al., 2006; Luo et al., 2013) (Fig. 5). Decreased expression of sFlt-1 in photo-receptor and pigment epithelial cells has been reported in AMD patients, suggesting that an increase in free VEGF may stimulate pathological angiogenesis in the retinas of these individuals. "
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    ABSTRACT: Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.
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    • "Importantly, expression of several short isoforms, which are known to be soluble, was confirmed. This finding may be an answer to a long-standing conundrum as to how the cornea maintains its avascularity and may provide further support for previously reported results [50]. This information could also partly explain angiogenic disturbances frequently observed in limbal stem cell deficiency (LSCD). "
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    ABSTRACT: Corneal epithelium is maintained throughout life by well-orchestrated proliferation of limbal epithelial stem cells (LESCs), followed by migration and maturation centripetally towards the ocular surface. Disturbance of LESCs can potentially lead to a blinding condition, which can be reversed by reconstitution of a functional LESC pool. The current clinical procedures are effective to some degree, however, deeper knowledge of the molecular interplay within the limbal niche is necessary to achieve a fully satisfactory patient outcome. The present study was thus undertaken to carry out a comprehensive transcriptome analysis of four distinct human limbal compartments, including basal limbal crypts (BLCs), superficial limbal crypts (SLCs), cornea, and the supporting stroma, with the aid of laser capture microdissection and deep RNA sequencing. The tissue harvest pipeline was rigorously optimized so that the exposure to cold ischemia would be less than five minutes. The global gene ontology analysis confirmed existence of primitive cells in BLCs, migratory and activated cells in SLCs, and differentiated cells in cornea. Interestingly, many significantly upregulated genes in SLCs mapped to processes involved in regulation of vasculature, such as sFLT1. In contrast, BLCs exhibited many genes mapping to neurogenic processes and processes related to cell development. The primitive nature of BLCs was, furthermore, confirmed by the KEGG pathway analysis, and some potential regulators of LESCs were revealed, such as Lrig1 and SOX9. The analysis also yielded comprehensive lists of uniquely expressed genes in both BLCs and cornea, which may be useful to identify possible biomarkers. In conclusion, the current investigation provides new insight into the relationship between distinct cell populations within the limbal niche, identifies candidates to be verified for novel biological functions, and yields a wealth of information for prospective data mining.
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