Abnormal uterine XXXX during progestin-only contraception may result from free radical-induced alterations in angiopoietin expression.

@entity1 @entity11796 @entity548 @entity3658 @entity26 @entity2121 @entity53 @entity519 @entity877 @entity1478 @entity1435
Abnormal uterine @entity548 is the leading indication for discontinuation of long-term progestin-only contraceptives (LTPOCs). Histological sections of endometria from LTPOC-treated @entity1 display abnormally enlarged blood vessels at @entity548 sites. @entity2121 , a trend toward reduced endometrial perfusion in LTPOC users has been reported in these @entity1 . We hypothesized that @entity519 /reperfusion-induced free radical production inhibits the expression of @entity3658 ( @entity3658 ), a vessel stabilizing factor, leaving unopposed the effects of endothelial @entity877 , a vessel-branching and permeability factor. Immunohistochemical studies confirmed selective decreases in stromal cell @entity3658 in LTPOC-exposed endometrium. To indirectly assess whether LTPOC enhances endometrial free radical production, immunostaining was conducted for the phosphorylated form of the stress-activated kinases SAPK/JNK and @entity1435 . These kinases were greatly increased in endometria from LTPOC-treated @entity1 . Interestingly, the endothelial cells but not the stromal cells displayed enhanced immunostaining for the phosphorylated mitogen-activated kinase (pMAPK) after LTPOC treatment. To further examine the effects of progestin, @entity519 , and reactive @entity26 species (ROS) on the regulation of @entity3658 and @entity877 as well as the activation of MAPK, SAPK/JNK, and @entity1435 by the relevant cell types, we conducted in vitro studies with cultured @entity1 endometrial stromal cells (HESCs) and @entity1 endometrial endothelial cells (HEECs). Cultures of HESCs were treated with vehicle control, @entity53 (E(2)), or with @entity11796 +/- E(2) under @entity519 and normoxic conditions. Although @entity11796 but not E(2) increased @entity3658 expression, @entity519 greatly decreased @entity3658 protein and mRNA expression. In contrast, HESCs did not appear to express @entity877 protein or mRNA. Conversely, cultured HEECs did not appear to express @entity3658 , but expressed @entity877 , the levels of which were significantly increased by @entity519 . @entity519 also induced the phosphorylation of SAPK/JNK and @entity1435 in both cultured HESCs and HEECs. Moreover, ROS such as that observed after @entity519 /reperfusion resulted in the activation of SAPK/JNK and @entity1435 in HESCs and HEECs and inhibited @entity3658 in cultured HESCs. These effects could be blocked by @entity26 radical scavengers. Consistent with the in vivo studies, MAPK was activated after ROS treatment in HEECs but not in HESCs. Our findings suggest that LTPOC-induced @entity1478 as a result of @entity519 /reperfusion-induced free radicals that directly damage vessels and alter the balance of @entity3658 and @entity877 to produce the characteristic enlarged and permeable vessels that are prone to @entity548 .
