Age alters cerebrovascular inflammation and effects of estrogen.
In young adult females, estrogen treatment suppresses the cerebrovascular inflammatory response; this is mediated in part via NF-kappaB, a key regulator of inflammatory genes. To examine whether age modifies effects of estrogen on vascular inflammation in the brain, female rats, 3 and 12 mo of age, were ovariectomized; half were treated with estrogen for 4 wk. Cerebral blood vessels were isolated from the animals at 4 and 13 mo of age. Inflammation was induced by LPS, either injected in vivo or incubated with isolated vessels ex vivo. Basal levels of cytoplasmic NF-kappaB were significantly higher in cerebral vessels of young rats, but the ratio of nuclear to cytoplasmic levels was greater in middle-aged animals. LPS exposure increased nuclear NF-kappaB DNA binding activity, protein levels of inducible nitric oxide synthase and cyclooxygenase-2, and production of nitric oxide and PGE(2) in cerebral vessels. All effects of LPS were markedly greater in vessels from the older animals. Estrogen significantly inhibited the LPS-induced increase in NF-kappaB DNA binding activity in cerebral vessels from animals at both ages. In 4-mo-old rats, estrogen also significantly suppressed LPS induction of inducible nitric oxide synthase and cyclooxygenase-2 proteins, as well as production of nitric oxide and PGE(2). In contrast, in 13-mo-old females, estrogen did not significantly affect these indexes of cerebrovascular inflammation. Thus the protective, anti-inflammatory effect of estrogen on cerebral blood vessels that is observed in young adults may be attenuated in aged animals, which exhibit a greater overall cerebrovascular response to inflammatory stimuli.
Sunday
Lorraine
L
Department of Pharmacology, School of Medicine, University of California-Irvine, Irvine, CA 92697-4625, USA.
Osuna
Christa
C
Krause
Diana N
DN
Duckles
Sue P
SP
D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods; D010052:Ovariectomy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016896:Treatment Outcome; D020293:Vasculitis, Central Nervous System / Q000188:drug therapy* / Q000378:metabolism*
D016207:Cytokines; D017382:Reactive Oxygen Species; D004958:Estradiol