The mechanisms that regulate N-cadherin gene expression remain largely unknown, though they have been shown to be cAMP dependent.
20 21 In bovine and human CE cells, cAMP production is stimulated by vasoactive intestinal peptide (VIP),
22 suggesting that VIP may play a role in the modulation of N-cadherin expression in CE cells. VIP is a 28-amino acid neuropeptide that binds to two types of adenylyl cyclase stimulatory heterotrimeric G protein–coupled receptors (VPAC1 and VPAC2) and transduces signal through cAMP-dependent and -independent pathways.
23 24 25 While VIP is widely distributed in the central and peripheral nervous systems, including those in the eye,
26 27 and in the immune system,
28 we have previously reported that VIP mRNA and protein are also expressed in the CE cells in human and bovine corneas.
29 Recently, we have reported that VIP expression in human CE cells in situ is upregulated by the injury factor ciliary neurotrophic factor (CNTF),
30 which in turn is an autocrine released by CE cells surviving oxidative stress ex vivo.
31 Furthermore, VIP is present and identified as one of the immunosuppressive factors in the aqueous humor,
32 33 34 the fluid that fills the anterior and posterior chambers of the eye and that constantly bathes the CE cells in vivo. Therefore, through modulation of the cAMP level, the endogenous VIP in CE cells may play a role in regulating the N-cadherin level. Thus, in addition to being a trophic factor of CE cells under acute oxidative stress,
29 VIP may also play a role as a differentiation-promoting factor by inducing N-cadherin synthesis in CE cells, in agreement with the role of VIP found in neuroendocrine differentiation,
35 36 neurite genesis and remodeling,
37 38 and melanin genesis in retinal pigment epithelium.
39