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H. Pan, N. Nguyen, H. Yoshida, F. Bentzien, I. Struman, R. Weiner, M.B. Grant; The 16 kDa Fragment of Prolactin Modulates Endothelial Cell Apoptosis and In Vivo Retinal Angiogenesis . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2899.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The 16 kDa fragment of human prolactin (16K hPRL) is a potent specific antiangiogenic factor in vivo and in vitro. 16K hPRL inhibits VEGF- and bFGF-induced capillary endothelial cell growth by blocking activation of the MAPK signaling cascade and inducing apoptosis. However, the effect of 16K hPRL on vascular cells of the retina has not been evaluated. We compared the effect of 16K hPRL to the potent antiangiogenic agent endostatin on human retinal endothelial cell (HREC) apoptosis and evaluated the effect of 16K hPRL on retinal neovascularization using the mouse model of ischemia-induced retinopathy. Methods: Varying concentration (5, 10, and 20 nM) of 16K hPRL were added to HREC and the level of DNA fragmentation associated with apoptosis was evaluated by measuring the levels of cytosolic mono- and oligonucleosomes using an ELISA assay. The 16K hPRL-encoding sequence was inserted into an adenovirus vector (Ad-16K) and expression of the secreted form of 16K hPRL was verified by Western analysis following infection of HCT116 cells. Ad-16K or Ad-null vectors were intravitreally injected in one-day-old mice. The mice were then subjected to the neonatal oxygen induced retinopathy model. Eyes were sectioned and neovascularization scored by light microscopy. Results: 16K hPRL activated HREC apoptosis and the effect of 5 nM 16K hPRL was comparable to that seen with 0.5 µM endostatin. Eyes injected with Ad-16K showed a reduction in pre-retinal neovascularization of 59.7 ± 20.0% (p=4.1X10-10) when compared to uninjected controls, while eyes injected with Ad-Null showed no significant difference when compared to uninjected controls (p=0.3). Conclusions: 16K hPRL is a potent apoptotic agent in HREC. Using a gene therapy approach 16K hPRL effectively inhibits retinal neovascularization in the mouse model of ischemia-induced retinopathy. These findings support the potential of 16 K hPRL as a therapeutic agent for treatment of proliferative retinopathies.
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