Adrenomedullin Receptor Overexpressing Mice Provide a New Mouse Model for Primary Angle–Closure Glaucoma

Abstract

Purpose: : Glaucoma is a leading cause of blindness. Here, we have investigated the role of the potent smooth muscle relaxing peptide adrenomedullin (AM) in the pathophysiology of angle–closure glaucoma (ACG) in transgenic mice that overexpress in the pupillary sphincter muscle an AM receptor that consists of heterodimeric calcitonin receptor–like receptor (CLR)/receptor–activity–modifying protein (RAMP)2.

Methods: : The expression of AM and of the AM receptor was immunohistochemically analysed on sections of eyes of ACG patients and of unaffected eyes. In the transgenic mice the CLR was overexpressed in the pupillary sphincter muscle under control of an α–actin promoter. AM signalling in target cells was visualised by phospho–CREB immunostaining. Pupillary constriction in the absence and presence of the AM antagonist, AM (20–50) was investigated and intraocular pressure (IOP) was measured by indentation tonometry. Morphological changes in the eyes of CLR–transgenic mice were studied by standard histology and with electron microscopy. Eyes of wild–type littermates were used in control experiments.

Results: : Increased levels of AM were recognized in the ciliary body of patients with angle–closure glaucoma. Moreover, CLR/RAMP2 AM receptors were located in the pupillary sphincter muscle. Overexpression of the CLR in the pupillary sphincter muscle of mice enhanced AM signalling that resulted in chronic relaxation. As a consequence, anterior synechia and closure of the anterior chamber angle occurred between 4 and 12 weeks of age. Obstruction of aqueous outflow increased the IOP and led to a progressive loss of RGC, much like in human PACG.

Conclusions: : The CLR–transgenic mice are an attractive animal model to study human ACG.

Keywords: receptors • gene/expression • intraocular pressure