Pathophysiological function of endogenous calcitonin gene-related peptide in ocular vascular diseases

  • Am J Pathol. 2015 Jun;185(6):1783-94. doi: 10.1016/j.ajpath.2015.02.017.
Yuichi Toriyama  1 ,  Yasuhiro Iesato  1 ,  Akira Imai  1 ,  Takayuki Sakurai  2 ,  Akiko Kamiyoshi  2 ,  Yuka Ichikawa-Shindo  2 ,  Hisaka Kawate  2 ,  Akihiro Yamauchi  2 ,  Kyoko Igarashi  2 ,  Megumu Tanaka  2 ,  Tian Liu  2 ,  Xian Xian  2 ,  Liuyu Zhai  2 ,  Shinji Owa  2 ,  Toshinori Murata  3 ,  Takayuki Shindo  4
Affiliations
  • 1. Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan; Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
  • 2. Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan.
  • 3. Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan.
  • 4. Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Nagano, Japan. Electronic address: [email protected].
PMID: 25857228 DOI: 10.1016/j.ajpath.2015.02.017
Abstract

Calcitonin gene-related peptide (CGRP; official name CALCA) has a variety of functions and exhibits both angiogenic and anti-inflammatory properties. We previously reported the angiogenic effects of the CGRP family peptide Adrenomedullin in oxygen-induced retinopathy; however, the effects of CGRP on ocular angiogenesis remain unknown. Herein, we used CGRP knockout (CGRP(-/-)) mice to investigate the roles of CGRP in ocular vascular disease. Observation of pathological retinal angiogenesis in the oxygen-induced retinopathy model revealed no difference between CGRP(-/-) and wild-type mice. However, much higher levels of the CGRP Receptor were present in the choroid than the retina. Laser-induced choroidal neovascularization (CNV), a model of exudative age-related macular degeneration, revealed more severe CNV lesions in CGRP(-/-) than wild-type mice, and fluorescein angiography showed greater leakage from CNV in CGRP(-/-). In addition, macrophage infiltration and tumor necrosis factor (TNF)-α production were enhanced within the CNV lesions in CGRP(-/-) mice, and the TNF-α, in turn, suppressed the barrier formation of retinal pigment epithelial cells. In vivo, CGRP administration suppressed CNV formation, and CGRP also dose dependently suppressed TNF-α production by isolated macrophages. From these data, we conclude that CGRP suppresses the development of leaky CNV through negative regulation of inflammation. CGRP may thus be a promising therapeutic agent for the treatment of ocular vascular diseases associated with inflammation.

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