Estrogen deprivation and estrogen receptor α antagonism decrease DSS colitis in female mice.

The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium-induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200-fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo-oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation.

Distinctive effects of SGLT2 inhibitors on angiogenesis in zebrafish embryos.

Sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin has been found to increase the risk for lower-limb amputations in type 2 diabetics about two-fold. Conversely, empagliflozin and dapagliflozin do not display a similar effect. A question arises whether the increased risk for minor amputations is associated only with canagliflozin or whether it is a class effect of SGLT2 inhibitors. Defective angiogenesis has a role in amputations. We compared the effects of empagliflozin, dapagliflozin and canagliflozin on angiogenesis in vivo using zebrafish model, and in vitro using human umbilical vein endothelial cells (HUVECs). The effects of SGLT2 inhibitors on the formation of intersegmental blood vessels (ISVs) of the zebrafish embryos were clarified. Additionally, transcriptome analysis was performed to explore whether putative angiogenesis-associated genes are differentially regulated by SGLT2 inhibitors. The effects of SGLT2 inhibitors on the viability of HUVECs were examined. We noticed that especially empagliflozin and also dapagliflozin significantly accelerated the formation of ISVs of zebrafish embryos. In contrast, canagliflozin was not able to stimulate ISV formation, and at high concentration, it was lethal to the embryos. Transcriptome analysis demonstrated that in empagliflozin-treated embryos compared to canagliflozin-treated embryos seven genes previously shown to contribute to angiogenesis were upregulated, and four downregulated. Canagliflozin at high concentrations, but not empagliflozin or dapagliflozin, decreased the viability of HUVECs and disrupted their capability to sprout. SGLT2 inhibitors differed in their effects on angiogenic processes in zebrafish embryos and on the viability of HUVECs suggesting that the risk of SGLT2 inhibitors for peripheral amputations likely differs.