Elevated Serum Prolactin Levels Protect Against VEGF-Induced Retinal Vasopermeability by Increasing Retinal Vasoinhibins

Abstract

Purpose: : The hormone prolactin (PRL) is proteolytically cleaved to vasoinhibins (Vi), a family of peptides that inhibit VEGF-induced retinal vasopermeability (RVP) (JCI 118:2291, 2008). Here, we investigate whether an increase in circulating PRL could reduce VEGF-induced RVP by increasing Vi in the retina.

Methods: : Hyperprolactinemia was induced in Wistar rats by placing two anterior pituitary grafts under the kidney capsule for 15 days. PRL receptor-null mice were used to investigate the mechanism mediating the incorporation of systemic PRL into the eye. The levels of serum PRL and retinal Vi were measured by RIA and Western blot, respectively. Hyperprolactinemic and control rats were injected intravitreally with VEGF (300 ng), or with 2 µl of vehicle (PBS). RVP was evaluated by fluorescein angiography and by the Evans blue method.

Results: : Higher systemic levels of PRL and retinal Vi (six-fold and three-fold, respectively) were found in anterior pituitary-grafted rats compared to non-grafted controls. Injection of grafted rats with the dopamine agonist bromocriptine reduced circulating PRL and retinal Vi to basal levels. PRL receptor-null mice, known to be hyperprolactinemic, displayed 1000-fold higher levels of circulating PRL, but levels of retinal Vi similar to those in wild-type littermates, suggesting that the PRL receptor mediates the ocular incorporation of PRL, which is subsequently cleaved to Vi. Intravitreal VEGF caused lower RVP and less extensive vascular leakage areas in the retina of hyperprolactinemic rats than in the normoprolactinemic counterparts.

Conclusions: : High levels of serum PRL lead to the accumulation of Vi in the retina and reduce RVP in response to VEGF. These findings support the hypothesis that hyperprolactinemia, by serving as a source of ocular Vi, protects against excessive RVP and may thus represent a novel therapeutic strategy for diabetic macular edema and the various proliferative retinopathies.

Keywords: diabetic retinopathy • vascular endothelial growth factor • growth factors/growth factor receptors