Oxidative stress and inflammation in cerebrovascular system: Modulation by ovarian steroids and age

Oxidative stress and inflammation are implicated in many age related disorders including stroke, atherosclerosis, and Alzheimer's. An insufficient balance between these stressors and protective antioxidants and anti-inflammatory mechanisms may be a contributing factor. Age related disease is on the rise following menopause. This can be due in part to the depletion of ovarian steroid production. Thus, this dissertation examined the effects of ovarian steroids on oxidative stress and inflammation in cerebrovasculature.; Chapter 2 describes how the 17beta-estradiol and progestagens differentially modulate vascular proinflammatory factors, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). Exposure to endogenous or exogenous estrogen suppressed cerebrovascular inflammation, while progestagens have opposing effect. Suggesting that this vasoprotective benefit of estrogen may be diminished in the presence of progestagens.; Chapter 3 demonstrates estrogen suppression of induced cerebral vascular COX-2 following middle cerebral artery occlusion (MCAO) in mice. MCAO resulted in an increase in COX-2 levels in blood vessels isolated from ipsilateral hemisphere. Additionally, COX-2 levels were higher in OVX compared to intact females and OVX females given E. Thus, E elicits anti-inflammatory effects post ischemic injury in mice.; Chapter 4 addresses the influence of age on the anti-inflammatory effect of estrogen in the cerebrovasculature. E suppresses LPS induction of iNOS and COX-2 and their respective reaction products, NO and PGE2, through the NF-kB signaling pathways in 4 months rats. This anti-inflammatory effect of E was altered in 13 months rats. We demonstrated that the anti-inflammatory effect of estrogen diminishes with age.; Chapter 5 describes the effect of estrogen on mitochondria-dependent oxidative stress and energy efficiency. We demonstrated that estrogen significantly decreased mitochondrial ROS production in human brain microvascular endothelial cells treated with estrogen. Additionally, we also demonstrated that estrogen dramatically increased mitochondrial energy efficiency by increasing levels of cytochrome c, an enzyme involved in augmenting energy efficiency and acting as an antioxidant.; In conclusion, estrogen has both anti-inflammatory and antioxidant roles in the cerebrovasculature. This may contribute to why women live longer compared to their male counterparts. Since we demonstrated that the anti-inflammatory effect of estrogen is diminished by progesterone and age, it is possible that the controversial role of hormone replacement therapy (HRT) in clinical studies failed to show vasoprotective effect of estrogen in aged women subjects taking combination of estrogen and progesterone agonist in HRT.