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1 Department of Pharmacology, University of California, Irvine, Irvine, California, USA
* To whom correspondence should be addressed. E-mail: spduckle{at}uci.edu.
The potential benefit of ovarian hormone replacement therapy in cerebrovascular disease is well supported by experimental observations but not by recent large randomized clinical trials. This discrepancy points out the need for better understanding of the vascular actions of ovarian hormones as well as medroxyprogesterone acetate (MPA), a synthetic analog of progesterone (P) widely prescribed in combination with estrogens. Therefore, we investigated whether in vivo exposure to 17-
estradiol (E) and/or P or MPA modifies inflammation in the cerebral vasculature, a key process in the evolution of ischemic brain injury. Female rats were injected (i.p.) with lipopolysaccharide (LPS) to induce inflammation, and 6 h later brains were taken for blood vessel isolation and Western blot analysis of the inflammatory enzymes, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). In ovariectomized females (O), LPS induced cerebrovascular iNOS and COX-2; however this effect was significantly decreased when O animals were treated 3 wk with E. In contrast, treatment of O females with either MPA or P exacerbated the cerebrovascular inflammatory response to LPS. In intact females, LPS induction of iNOS and COX-2 in cerebral vessels was found to vary with the stage of the estrous cycle; LPS had the greatest effect during estrus when circulating estrogen is low and progesterone is high. Thus exposure to endogenous or exogenous ovarian hormones appears to modulate cerebrovascular inflammation. Anti-inflammatory effects of estrogen would attenuate ischemic brain injury; however this vasoprotective benefit may be diminished in the presence of progestagens.
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