Abstract
Pituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide having trophic and protective functions in neural tissues, including the retina. Previously, we have shown that intravitreal PACAP administration can maintain retinal structure in the animal model of retinopathy of prematurity (ROP). The purpose of this study is to examine the development of ROP in PACAP-deficient and wild-type mice to reveal the function of endogenous PACAP. Wild-type and PACAP-knockout (KO) mouse pups at postnatal day (PD) 7 were maintained at 75% oxygen for 5 consecutive days then returned to room air on PD12 to develop oxygen-induced retinopathy (OIR). On PD15, animals underwent electroretinography (ERG) to assess visual function. On PD16, eyes were harvested for either immunohistochemistry to determine the percentage of the central avascular retinal area or molecular analysis to assess angiogenesis proteins by array kit and anti-apoptotic protein kinase B (Akt) change by western blot. Retinas of PACAP-deficient OIR mice showed a greater central avascular area than that of the wild types. ERG revealed significantly decreased b-wave amplitude in PACAP KO compared to their controls. Several angiogenic proteins were upregulated due to OIR, and 11 different proteins markedly increased in PACAP-deficient mice, whereas western blot analysis revealed a reduction in Akt phosphorylation, suggesting an advanced cell death in the lack of PACAP. This is the first study to examine the endogenous effect of PACAP in the OIR model. Previously, we have shown the beneficial effect of exogenous local PACAP treatment in the rat OIR model. Together with the present findings, we suggest that PACAP could be a novel retinoprotective agent in ROP.
Highlights
Premature birth may come together with diseases that compromise future life quality, such as retinopathy of prematurity (ROP)
Age-related loss of lacrimal gland function and accelerated retinal aging have been described (Kovacs-Valasek et al 2017; Nakamachi et al 2016). These results clearly show that endogenously present Pituitary adenylate cyclase–activating polypeptide (PACAP) reacts as a stress-response peptide necessary for protection against different retinal insults
Our observation was that retinopathic mice lacking PACAP showed a deteriorated vascularization, a disrupted cytokine balance, and a decreased cell protective mechanism, as well as visual functional disturbances. These results suggest that endogenous PACAP is part of the protective machinery in this retinopathy model
Summary
Premature birth may come together with diseases that compromise future life quality, such as retinopathy of prematurity (ROP). Preterm infants with extreme retinal immaturity and Pituitary adenylate cyclase–activating polypeptide (PACAP) is a 38-amino acid pleiotropic peptide known to act as a neurotransmitter, neuromodulator, and neurotrophic factor (Nakamachi et al 2011; Ciranna and Costa 2019; Johnson et al 2020; Gargiulo et al 2020). PACAP consistently exerts protective effects in the nervous system and peripheral organs by mediating various physiological processes (Martinez-Rojas et al 2021; Nonaka et al 2020; Toth et al 2020). The protective role of PACAP can be observed in the retina against hypoxic, mechanical, and chemical injuries as reviewed by Nakamachi and colleagues and by our group (Atlasz et al 2016; Nakamachi et al 2012; D’Amico et al 2021). PACAP is neuroprotective in diabetic retinopathy (D’Amico et al 2021). We have recently shown the potentially positive effect of intravitreally given PACAP injection on the vascular changes in the rat OIR model (Kvarik et al 2016)
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