Role of prostaglandin E receptor subtypes EP2 and EP4 in autocrine and paracrine functions of vascular endothelial growth factor in the inner ear

Background: The physiological effects of prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) are mediated by the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, and the respective agonists have been purified. PGE1 and PGE2 can increase the production of vascular endothelial growth factor (VEGF), particularly through EP2 and EP4. The biological effects of VEGF are mediated by the phosphotyrosine kinase receptors fms-related tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1). Here we examined the effects of EP2 and EP4 agonists on the production of VEGF proteins and VEGF messenger RNAs (mRNAs) in the inner ear, using an enzyme-linked immunosorbent assay and the real-time quantitative reverse transcription-polymerase chain reaction, respectively. We also examined the localization of EP2, VEGF, Flt-1, and Flk-1 in the cochlea by immunohistochemistry. Results: The expression of EP2 occurred in the cochlea, and the local application of an EP2 or EP4 agonist increased VEGF protein and VEGF mRNA levels in the inner ear. Furthermore, the intensity of the VEGF immunoreactivity in the spiral ganglion appeared to be increased by the local EP2 or EP4 agonist treatment. Immunoreactivity for Flt-1, and Flk-1 was found in the cochlear sensory epithelium, spiral ganglion, spiral ligament, and stria vascularis. Conclusions: These findings demonstrate that EP2 and EP4 agonists stimulate VEGF production in the inner ear, particularly in the spiral ganglions. Moreover, the Flt-1 and Flk-1 expression observed in the present study suggests that VEGF has autocrine and paracrine actions in the cochlea. Thus, EP2 and EP4 might be involved in the mechanisms underlying the therapeutic effects of PGE1 on acute sensorineural hearing loss via VEGF production.