Pathophysiological roles of adrenomedullin-2 in mouse model of ocular neovascularization

Abstract

Purpose : Adrenomedullin-2 (AM2) (or intermedin), a member of the calcitonin gene-related peptide family, is a peptide which possesses a variety of physiological functions. Previously, we reported the therapeutic possibility of intravitreal injection of AM2 by using laser-induced choroidal neovascularization model (LI-CNV) and oxygen-induced retinopathy model (OIR) in mice (ARVO 2020). In the present study, we further investigated the pathophysiological roles of AM2 in ocular neovascularization by systemic administration of AM2 in mice and using AM2 knockout mice (AM2-/-).

Methods : Wild-type mice (WT) were subjected to LI-CNV and the effect of systemic administration of AM2 using osmotic pump was investigated. Next, we established AM2 knockout mice (AM2-/-) by genome editing. LI-CNV was compared between AM2-/- and WT. To establish OIR, 7-day-old (P7) neonatal mice were subjected to hyperoxia (75% oxygen) for 5 days and returned to room air from P12 to 17. OIR was compared between AM2-/- and WT.

Results : In LI-CNV, AM2-administration significantly reduced the CNV area and αSMA immunostaining-positive fibrosis area, and significantly suppressed the expression of genes encoding VEGF-A, VEGF-R2, CD68, CTGF, and p22phox in the choroid. Contrary to AM2-administration, CNV area and fibrosis area were increased in AM2-/-. No apparent difference was observed in the retinal vessels of P7 and P12 between WT and AM-/-. There was no difference in the pathogenic angiogenic area of P17, however, the avascular area was reduced in AM2-/- compared to WT.

Conclusions : AM2 is expected as a therapeutic target of ocular neovascular diseases. AM2 may affect both retinal and choroidal neovascularization, but the effect may be more pronounced in the choroidal neovascularization.

This is a 2021 ARVO Annual Meeting abstract.