Activation of epidermal growth factor receptor signals induction of nitric oxide synthase-2 in human optic nerve head astrocytes in glaucomatous optic neuropathy.

Glaucoma is an optic neuropathy that is associated with elevated intraocular pressure in most patients. We have previously demonstrated that the mechanism by which pressure damages optic nerve axons involves excessive nitric oxide generated by inducible nitric oxide synthase (NOS-2). We have now found that activation of the epidermal growth factor receptor (EGFR) induces NOS-2 in astrocytes of the human optic nerve head (ONH) in vitro and EGFR is significantly upregulated and tyrosine phosphorylated in reactive astrocytes in human glaucomatous ONHs in vivo. Furthermore, in response to elevated hydrostatic pressure, EGFR rapidly becomes phosphorylated in the nucleus. This pressure-dependent activation of EGFR is necessary for NOS-2 induction. Our results suggest that activation and nuclear localization of EGFR may be needed for induction of NOS-2 in response to elevated intraocular pressure in glaucomatous optic neuropathy. Identification of this key signaling pathway provides new therapeutic approaches to pharmacological neuroprotection for glaucoma.