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Antonella N. Witmer, Harriet G. Blaauwgeers, Herbert A. Weich, Kari Alitalo, Gijs F. J. M. Vrensen, Reinier O. Schlingemann; Altered Expression Patterns of VEGF Receptors in Human Diabetic Retina and in Experimental VEGF-Induced Retinopathy in Monkey. Invest. Ophthalmol. Vis. Sci. 2002;43(3):849-857.
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purpose. The vascular endothelial growth factor (VEGF) family is involved in
vascular leakage and angiogenesis in diabetic retinopathy (DR) in the
eye, but may also have physiological functions. Based on the hypothesis
that differential VEGF receptor (VEGFR) expression in the retina is an
important determinant of effects of VEGF, this study was conducted to
investigate VEGFR expression in the diabetic retina and in an
experimental monkey model of VEGF-A–induced retinopathy.
methods. In retinas of 27 eyes of diabetic donors, 18 eyes of nondiabetic
control donors, and 4 monkey eyes injected with PBS or VEGF-A,
expression patterns of VEGFR-1, -2, and -3 in relation to leaky
microvessels, as identified by the marker pathologische anatomie
Leiden-endothelium (PAL-E) were studied by immunohistochemistry.
results. In control human retinas and retinas of PBS-injected monkey eyes, all
three VEGFRs were expressed in nonvascular areas, but only VEGFR-1 was
constitutively expressed in retinal microvessels. In diabetic
eyes, increased microvascular VEGFR-2 expression was found in
association with PAL-E expression, whereas microvascular VEGFR-3 was
present in a subset of PAL-E–positive cases. In VEGF-A–injected
monkey eyes, VEGFR-1, -2, and -3 and PAL-E were expressed in retinal
conclusions. The VEGFR-1, -2, and -3 expression patterns in control retinas suggest
physiological functions of VEGFs that do not involve the vasculature.
Initial vascular VEGF signaling may act primarily through VEGFR-1. In
diabetic eyes, expression of retinal VEGFR-2 and -3 is increased,
mainly in leaky microvessels, and VEGF-A induces vascular expression of
the VEGF-A receptor VEGFR-2 and the VEGF-C/D receptor VEGFR-3. These
findings indicate a dual role of VEGFs in the physiology and
pathophysiology of the retina and suggest that microvascular VEGFR-2
and -3 signaling by VEGFs occurs late in the pathogenesis of DR,
possibly initiated by high levels of VEGF-A in established
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