Adrenomedullin Suppresses Vascular Endothelial Growth Factor-Induced Vascular Hyperpermeability and Inflammation in Retinopathy.
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.
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
Akira
A
Imai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
Yuichi
Y
Toriyama
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
Yasuhiro
Y
Iesato
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
Kazutaka
K
Hirabayashi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Takayuki
T
Sakurai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Akiko
A
Kamiyoshi
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Yuka
Y
Ichikawa-Shindo
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Hisaka
H
Kawate
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Megumu
M
Tanaka
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Tian
T
Liu
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Xian
X
Xian
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Liuyu
L
Zhai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Kun
K
Dai
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Keiya
K
Tanimura
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Teng
T
Liu
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
Nanqi
N
Cui
Research Division, Japan Bio Products Co., Ltd., Tokyo, Japan.
Akihiro
A
Yamauchi
Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
Toshinori
T
Murata
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan. Electronic address: tshindo@shinshu-u.ac.jp.
Takayuki
T
Shindo
D053607:Adrenomedullin / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000503:physiopathology*; D017097:Electric Impedance; D042783:Endothelial Cells / Q000502:physiology; D058449:Intravitreal Injections; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D012173:Retinitis / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; D053607:Adrenomedullin