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      Pathogenesis and classification of proliferative diabetic vitreoretinopathy.

      Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift für Augenheilkunde
      Diabetic Retinopathy, classification, diagnosis, etiology, Diagnosis, Differential, Disease Progression, Humans, Prognosis, Risk Factors, Vitreoretinopathy, Proliferative

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          Abstract

          To review the current knowledge regarding the pathogenesis of proliferative diabetic vitreoretinopathy (PDVR) and to present recommendations for its clinical staging. Focused literature review and authors' clinical experience. Although several biochemical mediators may be responsible for the pathogenesis of PDVR, no common biochemical pathway exists. Of those mediators, vascular endothelial growth factor is the one most studied so far. However, since in proliferative diabetic retinopathy (PDR) the thickened posterior vitreous cortex is one of the main factors in the development of proliferations, a consequent shrinkage of the posterior vitreous cortex leads to hemorrhages and tractive retinal detachments. Therefore, PDR should be called PDVR. In consequence, the authors present a new morphological classification of PDVR. There is no consensus about the biochemical pathway responsible for the progression of PDVR. Although several classifications are described in the literature, the classification suggested here is important in the judgment of, the communication about and the therapy of diabetic retinopathy. Furthermore, it is the only reliable classification for predicting the surgical outcome in diabetics. Copyright (c) 2007 S. Karger AG, Basel.

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          Most cited references77

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          Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study

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            Molecular and biological properties of vascular endothelial growth factor.

            N Ferrara (1999)
            Vascular endothelial growth factor (VEGF) is a fundamental regulator of normal and abnormal angiogenesis. Recent evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis. Furthermore, VEGF is required for the cyclical blood vessel proliferation in the female reproductive tract and for longitudinal bone growth and endochondral bone formation. Substantial experimental evidence also implicates VEGF in pathological angiogenesis. Anti-VEGF monoclonal antibodies or other VEGF inhibitors block the growth of many tumor cell lines in nude mice. Furthermore, the concentrations of VEGF are elevated in the aqueous and vitreous humors of patients with proliferative retinopathies such as the diabetic retinopathy. In addition, VEGF-induced angiogenesis results in a therapeutic benefit in several animal models of myocardial or limb ischemia. Currently, both therapeutic angiogenesis using recombinant VEGF or VEGF gene transfer and inhibition of VEGF-mediated pathological angiogenesis are being pursued.
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              Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells.

              Vascular endothelial growth factor (VEGF) is a regulator of vasculogenesis and angiogenesis. To investigate the role of nitric oxide (NO) in VEGF-induced proliferation and in vitro angiogenesis, human umbilical vein endothelial cells (HUVEC) were used. VEGF stimulated the growth of HUVEC in an NO-dependent manner. In addition, VEGF promoted the NO-dependent formation of network-like structures in HUVEC cultured in three dimensional (3D) collagen gels. Exposure of cells to VEGF led to a concentration-dependent increase in cGMP levels, an indicator of NO production, that was inhibited by nitro-L-arginine methyl ester. VEGF-stimulated NO production required activation of tyrosine kinases and increases in intracellular calcium, since tyrosine kinase inhibitors and calcium chelators attenuated VEGF-induced NO release. Moreover, two chemically distinct phosphoinositide 3 kinase (PI-3K) inhibitors attenuated NO release after VEGF stimulation. In addition, HUVEC incubated with VEGF for 24 h showed an increase in the amount of endothelial NO synthase (eNOS) protein and the release of NO. In summary, both short- and long-term exposure of human EC to VEGF stimulates the release of biologically active NO. While long-term exposure increases eNOS protein levels, short-term stimulation with VEGF promotes NO release through mechanisms involving tyrosine and PI-3K kinases, suggesting that NO mediates aspects of VEGF signaling required for EC proliferation and organization in vitro.
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