PACAP and VIP Inhibit HIF‐1α‐Mediated VEGF Expression in a Model of Diabetic Macular Edema

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) exert a protective role against retinal injuries, including diabetic macular edema (DME). The macular damage is induced by hyperglycemia, which damages vessels supplying blood to the retina and induces hypoxia. The microenvironmental changes stimulate the expression of hypoxia-inducible factors (HIFs), which promote the choroidal endothelial cell transmigration across the retinal pigmented epithelium (RPE) into neurosensory retina, where they proliferate into new vessels under stimulation of the vascular endothelial growth factor (VEGF). In the present study, we have investigated whether PACAP and VIP prevent retinal damage by modulating the expression of HIFs, VEGF, and its receptors. In accord to our hypothesis, we have shown that both peptides are able to significantly reduce HIF-1α and increase HIF-3α expression in ARPE-19 cells exposed to hyperglycemic/hypoxic insult. This effect is also related to a reduction of VEGF and its receptors expression. Moreover, both peptides also reduce the activation of p38 mitogen-activated protein kinase (MAPK), a pro-apoptotic signaling pathway, which is activated by VEGFR-1 and 2 receptors. In conclusion, our study has further elucidated the protective role performed by PACAP and VIP, against the harmful combined effect of hyperglycemia/hypoxia characterizing the DME microenvironment. J. Cell. Physiol. 232: 1209-1215, 2017. © 2016 Wiley Periodicals, Inc.

Caffeine Prevents Blood Retinal Barrier Damage in a Model, In Vitro, of Diabetic Macular Edema

“…As previously demonstrated, the barrier breakdown is correlated to increased cellular death induced by the combinatorial action of hyperglycemia and hypoxia [He et al, ; Maugeri et al, ,]. Caffeine's role on programmed cell death seems ambiguous.…”

“…The experiments have been performed after 24 h exposure to this insult. As previously described, it represents the period where a significant damage to BRB has been detected [Maugeri et al, c,d]. The treatment with caffeine has been performed at 100 μM concentration because, in a previous study, it has represented the more efficacious dose to prevent programmed cell death [Nakaso et al, ].…”

PACAP and PAC1R are differentially expressed in motor cortex of amyotrophic lateral sclerosis patients and support survival of iPSC‐derived motor neurons

“…Most of its effects are mediated through the activation of PAC1R, whereas others are due to VPAC1 or VPAC2 receptors, which bind also VIP (Arimura, ; Arimura & Shioda, ; Zhou et al, ). PACAP is a pleiotropic molecule, involved in a wide range of physiological processes, including cell survival during neurodegenerative conditions, stress response and cell division (Canonico et al, ; Castorina et al, ; Castorina, Giunta, Mazzone, Cardile, & D'Agata, ; Castorina, Scuderi, D'Amico, Drago, & D'Agata, ; Cavallaro et al, , ; D'Agata & Cavallaro, ; D'Agata, Cavallaro, Stivala, Travali, & Canonico, ; D'Amico et al, , ; Giunta et al, ; Maino et al, ; Maugeri, D'Amico, & Gagliano, ; Maugeri, D'Amico, & Saccone, ; Scuderi et al, ). Moreover, it is known to act as a neurotransmitter and/or a neuromodulator in the peripheral and central nervous system (Jóźwiak‐Bębenista, Kowalczyk, & Nowak, ; Shioda et al, , ; Yang et al, ).…”

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

“…VEGF production and signaling are partly dependent on the induction of hypoxia inducible factor-1 alpha (HIF-1α) expression by mechanistic target of rapamycin (mTOR) [7, 8]. The inhibition of HIF-1α-mediated VEGF expression can suppress neovascularization [9]. …”