Adrenomedullin Suppresses Vascular Endothelial Growth Factor–Induced Vascular Hyperpermeability and Inflammation in Retinopathy

Abstract

Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.

Adrenomedullin surges are linked to acute episodes of the systemic capillary leak syndrome (Clarkson disease)

“…These results are similar to those of Imai et al , who recently found that ADM suppressed the barrier disruption induced by VEGF-A on retinal endothelial cell monolayers through effects on tight junctions. 28 In addition, we found that ADM’s effect on vascular barrier function was mediated by fortification of VE-cadherin-mediated cell-cell junctions. VE-cadherin is thought to be a master controller of endothelial integrity and regulates tight junction formation indirectly by controlling expression of component proteins claudin-5 and ZO1.…”

Development of a Novel Model of Central Retinal Vascular Occlusion and the Therapeutic Potential of the Adrenomedullin–Receptor Activity–Modifying Protein 2 System

“…Isolectin B4 staining has been previously used to visualize endothelial cells in the retinal vasculature. 25 Comparing images of FITC perfusion and isolectin B4 staining in retinal flat mounts after CRVO, the distributions of FITC and isolectin B4 positivity were found to differ somewhat ( Figure 5A). In images of FITC-perfused retinas, nonperfused areas could not be clearly visualized ( Figure 5A).…”

“…23,24 Exogenous administration of ADM suppresses vascular hyperpermeability and inflammation in a DR model. 25 These observations prompted us to investigate the relationship between ADM and CRVO.…”

The Role of Inflammation in Diabetic Retinopathy

“…Severe non-proliferative DR (NPDR) is characterized by increasing retinal oedema, venous abnormalities ("beading") ( Figure 6) and deposits of lipid-rich exudates often concentrated around the macula/fovea. Both PDR and macular edema ( Figure 6a) are driven by high local levels of hypoxia and release of VEGF (110,(113)(114)(115). Sight loss from macular edema is typical of T2D while intraocular haemorrhage and tractional retinal detachment are more common in T1D, although both causes of sight loss frequently occur in either type of diabetes.…”