Prolactin Decreases in the Circulation of Patients with Proliferative Diabetic Retinopathy: Relationship to Intraocular Vasoinhibins

Abstract

Purpose:: Vasoinhibins are a family of peptides derived from the hormone prolactin (PRL) that inhibit angiogenesis and vasodilation. Here, we investigate the systemic levels of PRL in association with the progression of diabetic retinopathy (DR) to determine whether circulating PRL could be a source of intraocular vasoinhibins.

Methods:: Serum PRL was evaluated by ELISA in 164 men (40 to 70 years) who were divided into non-diabetic and diabetic groups at various stages of retinopathy. Wistar rats were made hyperprolactinemic by placing pituitary grafts under the kidney capsule for 15 days, and PRL and vasoinhibins were measured in the vitreous humor by western blots. In addition, rats were injected intravitreally with 5 µg of PRL, and its conversion to vasoinhibins was evaluated in vitreous humor extracted 6 hours after injection. Finally, the vitreous humor of patients with DR was incubated with PRL for 72 hours to determine the activity of proteases able to generate vasoinhibins.

Results:: Serum PRL was significantly higher (p<0.05) in diabetic men without DR (37.1 ± 5.5 ng/ml; n=16) or with non-proliferative DR (42.2 ± 6.2 ng/ml; n=73) than in diabetics with proliferative DR (23.6 ± 2.3 ng/ml; n=44) and healthy controls (15.7 ± 2.1 ng/ml; n=31). Reduced PRL was observed in proliferative DR in both types 1 and 2 diabetes and was not associated with systemic complications like hypertension and nephropathy. PRL and vasoinhibins were two-fold higher in the vitreous humor of hyperprolactinemic rats than in controls. PRL injected intravitreally was processed to vasoinhibins and this conversion was abolished by the matrix metalloprotease inhibitor, GM6001. Finally, incubation of PRL with vitreous humor from patients with proliferative DR generated vasoinhibins.

Conclusions:: Serum PRL increases with diabetes but is reduced in proliferative RD. Hyperprolactinemia results in higher intraocular levels of PRL that is cleaved to vasoinhibins by matrix metalloproteases. Downregulation of systemic PRL may reduce intraocular vasoinhibins and contribute to the progression of DR.

Keywords: diabetic retinopathy • growth factors/growth factor receptors • proteolysis