June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Adrenomedullin reduces VEGF-induced retinal vascular hyperpermeability.
Author Affiliations & Notes
  • Akira Imai
    Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Yuichi Toriyama
    Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Yasuhiro Iesato
    Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Takayuki Sakurai
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Akiko Kamiyoshi
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Yuka Ichikawa-Shindo
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Hisaka Kawate
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Takayuki Shindo
    Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan
  • Toshinori Murata
    Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan
  • Footnotes
    Commercial Relationships Akira Imai, None; Yuichi Toriyama, None; Yasuhiro Iesato, None; Takayuki Sakurai, None; Akiko Kamiyoshi, None; Yuka Ichikawa-Shindo, None; Hisaka Kawate, None; Takayuki Shindo, None; Toshinori Murata, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2296. doi:
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      Akira Imai, Yuichi Toriyama, Yasuhiro Iesato, Takayuki Sakurai, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Takayuki Shindo, Toshinori Murata; Adrenomedullin reduces VEGF-induced retinal vascular hyperpermeability.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2296.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Purpose:<br /> Diabetic macular edema, caused by the retinal microvascular changes that compromise blood-retinal barrier (BRB), is a major cause of visual dysfunction. Adrenomedullin (AM) is an endogenous peptide first identified as a strong vasodilating molecule. We showed that AM knockout mice (AM-/-) are embryonic lethal with abnormal vascular development and first proved that AM also plays important roles in vascular integrity. AM is also expressed in eyes and upregulated in various eye diseases. However, most of the pathophysiological significance is unknown. In this study, we investigated the effect of AM on retinal vascular hyperpermeability.

Methods: Methods:<br /> AM (10-7M) or vehicle (control) was administered to wild-type C57BL/6 mice (WT) and Kimba mice using subcutaneous osmotic pumps (0.5μl/h) for 2 weeks. The integrity of the BRB was quantified by Evans blue technique (EB) and Confocal Scanning-Laser Ophthalmoscopy (SLO) in Fluorescein Angiography (FA). Retinal neovascularization and avascular area were evaluated using flat-mount specimens of the mouse retina stained with isolectin B4. Next, using human umbilical vein endothelial cell (HUVEC), AM’s effect on the barrier function was studied by measuring the transendothelial electrical resistance (TEER) and the permeability of FITC-dextran across the endothelial cell monolayer. The expression of tight junction proteins was analyzed by immunohistochemistry and immunoblotting.

Results: Results:<br /> In Kimba mice, which overexpress hVEGF165 in their retinas, BRB breakdown with enhanced vascular permeability was observed. On the other hand, exacerbation of FA leakage grade in Kimba mice was rescued by the exogenous administration of AM. In vitro analysis proved that AM-treatment elevated HUVEC TEER dose-dependently. Moreover, AM reversed VEGF-induced TEER reduction.

Conclusions: Conclusions:<br /> These results suggest that AM attenuates BRB breakdown induced by VEGF165. Our observation may provide a basis for novel therapeutic approach to ocular vascular diseases.

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