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Mayda Ramirez, Jorge Aranda, Edith Arnold, Nundehui Diaz-Lezama, Carlos Alvarez-Guzman, Yazmin Macotela, Gonzalo Martinez de la Escalera, Carmen Clapp; Matrix Metalloproteinases in the Vitreous Cleave Prolactin to Vasoinhibins. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4890.
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Matrix metalloproteinases (MMPs) cleave the hormone prolactin (PRL) to generate vasoinhibins, a family of N-terminal PRL fragments with antiangiogenic effects. Circulating PRL increases in diabetes and leads to the accumulation of retinal vasoinhibins, which inhibit VEGF- and diabetes-induced vasopermeability in the retina (Diabetes 59:3192, 2010). Here, we investigate whether MMPs that cleave PRL to vasoinhibins are present in the vitreous and if such proteolysis is affected by VEGF.
Four µl of PRL (5 µg), alone or together with VEGF (300 ng), was injected intravitreally into the eyes of rats in the absence or presence of the MMP inhibitor, galardin (10 µM). The presence of vasoinhibins in the vitreous was evaluated at different time points by Western blot.
PRL injected intravitreally was partially converted to vasoinhibins, identified by their reaction with antibodies directed against the N-terminus, but not the C-terminus, of PRL. Proteolysis was detected 30 minutes and up to 6 hour after PRL injection and was prevented by the co-injection of galardin. The intravitreal co-injection of PRL and VEGF promoted the degradation of PRL and vasoinhibins, and this effect was prevented by galardin.
These results reveal that MMPs present in the vitreous generate and also degrade vasoinhibins. The balance between these proteolytic actions may help maintain the quiescent state of retinal blood vessels under physiological conditions but may also contribute to pathological vascular alterations in diabetic retinopathy.
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