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. Epub 2015 Apr 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / genetics
  • Calcitonin Gene-Related Peptide / metabolism*
  • Choroidal Neovascularization / genetics
  • Choroidal Neovascularization / metabolism*
  • Choroidal Neovascularization / pathology
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, Calcitonin Gene-Related Peptide / metabolism
  • Retina / metabolism*
  • Retina / pathology
  • Retinal Vessels / metabolism*
  • Retinal Vessels / pathology

Substances

  • Receptors, Calcitonin Gene-Related Peptide
  • Calcitonin Gene-Related Peptide