Testosterone augments endotoxin-mediated cerebrovascular inflammation in male rats.
Activation of inflammatory mechanisms contributes to cerebrovascular pathophysiology. Male gender is associated with increased stroke risk, yet little is known about the effects of testosterone in the cerebral circulation. Therefore, we explored the impact of testosterone treatment on cerebrovascular inflammation with both in vivo and in vitro models of inflammation. We hypothesized that testosterone would augment the expression of two vascular markers of cellular inflammation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Using four groups of male rats [intact, orchiectomized (ORX), and ORX treated with either testosterone (ORXT) or the testosterone metabolite 17beta-estradiol (ORXE)], we determined effects of the sex hormones on cerebrovascular inflammation after intraperitoneal LPS injection. Western blot analysis showed that induction of inflammatory markers was increased in cerebral blood vessels from ORXT rats compared with intact or ORX rats. In contrast, in cerebral blood vessels from ORXE rats, there was a significant decrease in endotoxin-induced COX-2 and iNOS protein levels. Confocal microscopy of cerebral blood vessels from ORXT rats showed increased COX-2 and iNOS immunoreactivity in both endothelial and smooth muscle cells after LPS treatment. In vitro incubation with LPS also induced COX-2 in pial vessels isolated from the four animal treatment groups, with the greatest induction observed in ORXT vessels compared with the ORX and ORXE groups. Production of PGE2, a principal COX-2-derived prostaglandin end product, was also greatest in cerebral vessels isolated from ORXT rats. In conclusion, testosterone increases cerebrovascular inflammation; this effect may contribute to stroke differences between men and women.
Razmara
Ali
A
Dept. of Pharmacology, School of Medicine, Univ. of California-Irvine, Irvine, CA 92697-4625, USA.
Krause
Diana N
DN
Duckles
Sue P
SP
D000818:Animals; D015153:Blotting, Western; D002561:Cerebrovascular Disorders / Q000139:chemically induced / Q000473:pathology*; D015232:Dinoprostone / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004731:Endotoxins / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D018613:Microscopy, Confocal; D009919:Orchiectomy; D011506:Proteins / Q000032:analysis; D051381:Rats; D013268:Stimulation, Chemical; D013739:Testosterone / Q000633:toxicity*; D020293:Vasculitis, Central Nervous System / Q000139:chemically induced / Q000473:pathology*
D004731:Endotoxins; D011506:Proteins; D013739:Testosterone; D015232:Dinoprostone