Age alters cerebrovascular inflammation and effects of estrogen

Abstract

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.

E3 ubiquitin ligase NKLAM positively regulates macrophage inducible nitric oxide synthase expression

“…In WT and NKLAM-KO macrophages stimulated with LPS, p65 expression levels increased over time. Similar LPS-stimulated p65 expression kinetics has been observed in other experimental systems (Sunday, et al, 2007). The p65 expression kinetics is nearly identical in WT and NKLAM-KO BMDM; however, total p65 expression was lower in NKLAM-KO than in WT macrophages (Fig.…”

Endothelial damage due to impaired nitric oxide bioavailability triggers cerebral aneurysm formation in female rats

“…Sunday et al [25] showed that the protective, anti-inflammatory effect of estrogen on cerebral blood vessels in young adult rats was attenuated in aged animals; the ratio of nuclear to cytoplasmic levels of nuclear factor kappa B (NF-kB), a key regulator of inflammatory genes, was higher in aged than young rats. Sherwood et al [26] suggested that the benefit of natural estrogen supplementation on vascular endothelial function may be dependent on the postmenopausal age and that improved vascular function is elicited only in the early postmenopausal years.…”

Vascular Actions of Estrogens: Functional Implications

“…Interestingly, in rats estrogen has been shown to suppress vascular inflammatory responses to IL-1␤ and lipopolysaccharide treatments, and this response has also been shown to vary through the estrous cycle (Galea et al, 2002;Ospina et al, 2004;Sunday et al, 2006). An intriguing result is that this anti-inflammatory effect of estrogen is lost in older female animals (Miller et al, 2004a;Sunday et al, 2007).…”