Regulated expression of matrix metalloproteinases, inflammatory mediators, and endometrial matrix remodeling by 17beta-estradiol in the immature rat uterus.

BACKGROUND: Administration of a single physiological dose of 17beta-estradiol (E2:40 microg/kg) to the ovariectomized immature rat rapidly induces uterine growth and remodeling. The response is characterized by changes in endometrial stromal architecture during an inflammatory-like response that likely involves activated matrix-metalloproteinases (MMPs). While estrogen is known as an inducer of endometrial growth, its role in specific expression of MMP family members in vivo is poorly characterized. E2-induced changes in MMP-2, -3, -7, and -9 mRNA and protein expression were analyzed to survey regulation along an extended time course 0-72 hours post-treatment. Because E2 effects inflammatory-like changes that may alter MMP expression, we assessed changes in tissue levels of TNF-alpha and MCP-1, and we utilized dexamethasone (600 microg/kg) to better understand the role of inflammation on matrix remodeling. METHODS: Ovariectomized 21 day-old female Sprague-Dawley rats were administered E2 and uterine tissues were extracted and prepared for transmission electron microscopy (TEM), mRNA extraction and real-time RT-PCR, protein extraction and Western blot, or gelatin zymography. In inhibitor studies, pretreatment compounds were administered prior to E2 and tissues were harvested at 4 hours post-hormone challenge. RESULTS: Using a novel TEM method to quantitatively assess changes in stromal collagen density, we show that E2-induced matrix remodeling is rapid in onset (< 1 hour) and leads to a 70% reduction in collagen density by 4 hours. Matrix remodeling is MMP-dependent, as pretreatment with batimastat ablates the hormone effect. MMP-3, -7, and -9 and inflammatory markers (TNF-alpha and MCP-1) are transiently upregulated with peak expression at 4 hours post-E2 treatment. MMP-2 expression is increased by E2 but highest expression and activity occur later in the response (48 hours). Dexamethasone inhibits E2-modulated changes in collagen density and expression of MMPs although these effects are variable. Dexamethasone upregulates MMP-3 mRNA but not protein levels, inhibiting E2-induced upregulation of MMP-7, and -9, and MCP-1 mRNA and protein but not inhibiting the hormone-induced increase in TNF-alpha mRNA. CONCLUSION: The data demonstrate that E2-regulated endometrial remodeling is rapid in onset (<1 hour) and peak expression of MMPs and inflammatory mediators correlates temporally with the period of lowest stromal collagen density during uterine tissue hypertrophy.

Hypertension and the rate of cognitive decline in patients with dementia of the Alzheimer type.

Hypertension has been suspected of being associated with Alzheimer disease (AD). To study this problem, a case-control study investigating the association between hypertension and cognitive decline was conducted as a secondary analysis of data from more than 700 patients diagnosed with AD who had been randomly assigned to the placebo arm of a clinical trial. Additional analyses were undertaken to investigate the effects of baseline disease severity, age, gender, apolipoprotein genotype, and the use of antihypertensive medication in this population. This study found evidence of an association between hypertension and increased cognitive decline in AD patients over a 6-month period. After controlling for baseline disease severity, a pooled odds ratio (OR) was estimated to be 1.6 (95% confidence interval, 1.0-2.7) and found to be statistically significant (p = 0.048). Secondary analyses controlling for gender and apolipoprotein genotype showed no significant effect on the association between hypertension and cognitive decline. With regard to age, patients younger than 65 years with hypertension were more likely to have increased cognitive decline than patients of the same age without hypertension (odds ratio = 6.9, 95% confidence interval, 1.5-31.1; p = 0.005). Treatment with antihypertensives did not appear to provide protection from cognitive decline. Increased cognitive decline among those older than 65 years was comparable for hypertensive and normotensive subjects. This study, examining a large population of patients with AD, provides evidence that the rate in cognitive decline measured over a period of 6 months is accelerated by a state of hypertension in patients younger than 65 years.