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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Correlation of estrogen-induced uterine eosinophilia with other parameters of estrogen stimulation, produced with estradiol-17 β and estriol

Estradiol-17 β is a stronger estrogen than estriol for the genomic response of estrogens. Estriol is a stronger estrogen than estradiol-17 β for the estrogeninduced uterine eosinophilia and the 6h increase in the uterine wet weight13. © 1975, Birkhäuser Verlag. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Dynamics of Eosinophils in the Uterus after Oestrogen Administration

To investigate the role of the eosinophil leukocytes in the early oestrogenic responses in the uterus, the kinetics of oestrogen‐induced uterine eosinophilia and other parameters of oestrogen stimulation were studied at very early times. Uterine eosinophils increase as early as 5 min after an intravenous injection of oestradiol to immature rats, much earlier than several other changes in the early parameters of oestrogen stimulation. Large number of uterine eosinophils are found attached to the wall of small uterine blood vessels at early times. To elucidate the mechanisms involved in the specific attraction of eosinophils to the uterus in the presence of oestrogens, the in vivo localisation of oestrogens in the rat uterus at early times was studied using a radioautographic technique. Oestrogen receptors were found in the surface of eosinophils and in the wall of small uterine blood vessels. This simultaneous presence of both oestrogen receptors is proposed to explain the specific attachment of eosinophils to uterine blood vessels in the presence of oestrogens, which is the initial step toward eosinophil penetration into the uterus. Copyright © 1976, Wiley Blackwell. All rights reservedSCOPUS: ar.jinfo:eu-repo/semantics/publishe

New Concepts on the Action of Oestrogens in the Uterus and the Role of the Eosinophil Receptor System

Two receptor systems for oestrogens have been demonstrated in the uterus: the cytosol‐nuclear receptor system and the eosinophil receptor system. It has been proposed that the cytosol‐nuclear receptor system mediates the genomic response to oestrogens in the uterus, while the eosinophil receptor system is thought to mediate the uterine edema and other early oestrogenic responses in the uterus. Cortisol is known to decrease drastically the number of eosinophils in the blood and therefore to limit their availability for migration to the uterus. The present results show that cortisol also drastically reduces both the oestrogen‐induced uterine eosinophilia and the uterine wet weight responses, but does not interfere with the oestrogen‐induced uterine RNA and protein increases. Oestradiol‐17β has a higher affinity than oestriol for the cytosol‐nuclear receptors and is now found to be the more potent oestrogen in inducing the genomic activation in the uterus. Estriol has a higher affinity than oestradiol‐17β for the eosinophil receptors, and therefore, oestriol is the stronger oestrogen in inducing those oestrogenic effects which are mediated by the eosinophil receptor system. We conclude that the eosinophil receptor system for oestrogens is a new system, independent of Jensen's cytosol‐nuclear receptor system, and this eosinophil receptor system is involved in the mechanism of oestrogen action in the uterus. Copyright © 1976, Wiley Blackwell. All rights reservedSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effects of cortisol on uterine eosinophilia and other oestrogenic responses

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Effect of propranolol on various parameters of estrogen stimulation in the rat uterus

Pretreatment with propranolol does not modify the estrogen-induced uterine eosinophilia, the water imbibition effect, nor the increase in uterine RNA and protein content. This confirms the independence of these parameters from the estrogen-induced early increase in uterine cAMP, since, when observed, the latter is suppressed by propranolol pretreatment. © 1977 Experientia.SCOPUS: ar.jinfo:eu-repo/semantics/publishe