Expression of VEGF-related proteins in cultured human brain microvascular endothelial cells and pericytes after exposure to methylmercury

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  • Hirooka Takashi
    Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Yamamoto Chika
    Faculty of Pharmaceutical Sciences, Toho University Division of Bio-organometallics, Research Institute for Science and Technology, Tokyo University of Science
  • Yasutake Akira
    Graduate School of Science and Technology, Kumamoto University
  • Eto Komyo
    Health and Nursing Facilities for the Aged
  • Kaji Toshiyuki
    Faculty of Pharmaceutical Sciences, Tokyo University of Science Division of Bio-organometallics, Research Institute for Science and Technology, Tokyo University of Science

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Abstract

The localization of neuropathological lesions along deep sulci and fissures is one of the characteristics of a cerebrum damaged by methylmercury. Edematous changes in white matter have been proposed as the cause of the localization of lesions; however, the molecular mechanisms underlying methylmercury-induced edema remain unclear. Since the vascular endothelial growth factor (VEGF) system regulates vascular permeability and can be involved in the progression of edematous changes, we examined the effect of methylmercury on the expression of VEGF-related proteins in cultured human brain microvascular endothelial cells and pericytes. After methylmercury exposure, mRNA and protein levels of VEGF-A in pericytes and placenta growth factor (PlGF) and VEGF-receptor-1/-2 in endothelial cells were elevated. The induction of pericyte VEGF-A expression was independent of hypoxia-inducible factor-α and hypoxia-response element signaling. Taken together, these results suggest that methylmercury activates the VEGF system in brain microvessels in a paracrine fashion. When the activation occurs in narrow areas such as along the deep sulci in the cerebrum, hyperpermeability and subsequent edematous changes would cause a circulatory disturbance and result in neural cell damage. We propose this as a reason for the localization of the neuropathological lesions along the deep sulci and fissures in the cerebral cortex, such as the calcarine fissure, in patients with Minamata disease.

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