Catechol-o-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells.

CONTEXT: Development of optimal medicinal treatments of uterine leiomyomas represents a significant challenge. 2-Methoxyestradiol (2ME) is an endogenous estrogen metabolite formed by sequential action of CYP450s and catechol-O-methyltransferase (COMT). Our previous study demonstrated that 2ME is a potent antiproliferative, proapoptotic, antiangiogenic, and collagen synthesis inhibitor in human leiomyomas cells (huLM). OBJECTIVES: Our objectives were to investigate whether COMT expression, by the virtue of 2ME formation, affects the growth of huLM, and to explore the cellular and molecular mechanisms whereby COMT expression or treatment with 2ME affect these cells. RESULTS: Our data demonstrated that E(2)-induced proliferation was less pronounced in cells over-expressing COMT or treated with 2ME (500 nM). This effect on cell proliferation was associated with microtubules stabilization and diminution of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) transcriptional activities, due to shifts in their subcellular localization and sequestration in the cytoplasm. In addition, COMT over expression or treatment with 2ME reduced the expression of hypoxia-inducible factor -1alpha (HIF-1 alpha) and the basal level as well as TNF-alpha-induced aromatase (CYP19) expression. CONCLUSIONS: COMT over expression or treatment with 2ME stabilize microtubules, ameliorates E(2)-induced proliferation, inhibits ERalpha and PR signaling, and reduces HIF-1 alpha and CYP19 expression in human uterine leiomyoma cells. Thus, microtubules are a candidate target for treatment of uterine leiomyomas. In addition, the naturally occurring microtubule-targeting agent 2ME represents a potential new therapeutic for uterine leiomyomas.

A rat model of preeclampsia.

Preeclampsia/eclampsia is a disorder of human pregnancy that continues to exact significant maternal morbidity and mortality and fetal wastage. Therapy of these disorders has not changed in over 50 years and there are no proven preventive measures. We describe a model of the development of a syndrome in the pregnant rat that resembles preeclampsia, which results from the imposition of excessive volume expansion early in gestation. We administered desoxycorticosterone acetate (DOCA) to pregnant animals whose drinking water had been replaced with saline. We compared the results obtained in these animals with those resulting from the study of control, virgin animals, virgin animals receiving DOCA and saline, and normal pregnant (NP) animals. The virgin animals given DOCA and saline did not become hypertensive. The experimental paradigm in the DOCA plus saline pregnant (PDS) animals provides many of the phenotypic characteristics of the human disorder including the development of hypertension, proteinuria, and intrauterine growth restriction. In addition, the mean blood nitrite/nitrate concentration was reduced in the PDS rats compared with their NP counterparts. We propose that this model may prove to be useful in the study of the human condition.