Dihydrotestosterone stimulates cerebrovascular inflammation through NFκB, modulating contractile function

Rayna J. Gonzales, Sue P. Duckles, Diana N. Krause

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Our previous studies show that long-term testosterone treatment augments vascular tone under physiological conditions and exacerbates endotoxin-induced inflammation in the cerebral circulation. However, testosterone can be metabolized by aromatase to estrogen, evoking a balance between androgenic and estrogenic effects. Therefore, we investigated the effect of the nonaromatizable androgen receptor agonist, dihydrotestosterone (DHT), on the inflammatory nuclear factor-κB (NFκB) pathway in cerebral blood vessels. Cerebral arteries were isolated from orchiectomized male rats treated chronically with DHT in vivo. Alternatively, pial arteries were isolated from orchiectomized males and were exposed ex vivo to DHT or vehicle in culture medium. DHT treatment, in vivo or ex vivo, increased nuclear NFκB activation in cerebral arteries and increased levels of the proinflammatory products of NFκB activation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Effects of DHT on COX-2 and iNOS were attenuated by flutamide. In isolated pressurized middle cerebral arteries from DHT-treated rats, constrictions to the selective COX-2 inhibitor NS398 or the selective iNOS inhibitor L-nil, [L-N6-(Iminoethyl)lysine], were increased, confirming a functional consequence of DHT exposure. In conclusion, activation of the NFκB-mediated COX-2/iNOS pathway by the selective androgen receptor agonist, DHT, results in a state of vascular inflammation. This effect may contribute to sex-related differences in cerebrovascular pathophysiology.

Original languageEnglish (US)
Pages (from-to)244-253
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2009

Keywords

  • Androgen
  • Cerebral arteries
  • Dihydrotestosterone
  • Inflammation
  • Rats
  • Vascular tone

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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