Preeclampsia (PE) is a pregnancy-specific hypertensive syndrome that results in substantial maternal and fetal morbidities and mortalities. The exact cause of PE has not been fully demonstrated, but abnormal formation of the placenta has been considered. The placenta connects the developing fetus to...
Preeclampsia (PE) is a pregnancy-specific hypertensive syndrome that results in substantial maternal and fetal morbidities and mortalities. The exact cause of PE has not been fully demonstrated, but abnormal formation of the placenta has been considered. The placenta connects the developing fetus to the uterine wall, producing a large amount of steroid hormones to maintain pregnancy. Steroid hormones have been widely studied in PE serum. However, steroidogenesis by steoroidogenic enzymes in the placenta of PE has not well been established. In this study, we compared concentrations of steroid hormones in PE patients, in vivo PE models and in vitro PE models. Therefore, we first analyzed the mechanism and function of steroid hormones in PE patients. Pregnenolone (PG), progesterone (P4), dehydroepiandrosterone (DHEA), and estrogen (E2) concentrations tended to decrease in PE serum and placenta, and the results were significant for P4 and E2 in the serum of PE patients. Quantification of genes related with steroidogenesis in the placenta was examined, and expression of P4- and E2-synthesizing enzymes, testosterone 17‑β‑dehydrogenase 3 (HSD17B3) and 3 β‑hydroxysteroid dehydrogenase/δ5 4‑isomerase type 1 (HSD3B1), was reduced in PE placenta compared with normal placenta. Interestingly, aromatase (CYP19A1), an enzyme critical for production of E2, was up-regulated in PE placenta, suggesting steroidogenic enzymes are dynamically regulated and could affect symptoms of PE. We next examined the concentration of steroid hormone in vivo PE rat models. The rats were treated with N-Nitro-L-arginine methyl esterhydrocholride (L-NAME) and catechol-O-methyltransferase inhibitor (COMT-I) or underwent reduced uterine perfusion pressure (RUPP) operation. Serum and placenta were extracted to investigate relationship between PE and steroid hormones after the rats were sacrificed on GD 18. L-NAME, COMT-I, and RUPP groups showed PE-like symptoms, as previously studied. COMT-I increased the level of PG and DHEA in serum, while there was no effect on the placenta. L-NAME decreased the level of PG in serum and P4 in placenta. These results suggest that abnormal regulation of steroid hormones including PG, DHEA, P4 and E2 may be affected by PE conditions. To evaluate the regulatory mechanism in placenta cells, the production of steroid hormones through steroidogenesis was determined in human placental BeWo cells treated with L-NAME and COMT-I, or exposed to hypoxia. The in vitro PE models showed similar regulation of steroid hormones with PE patients by reducing production of E2 and P4. In addition, strongly decreased level of PG and DHEA was shown. These results suggest that the decrease of E2 and P4 in PE was because of reduction of their precursor hormones such as PG and DHEA from placenta, which was mediated via regulation of expression of steroidogenic enzymes including HSD17B3 and HSD3B1. Taken together, we found that steroid hormones such as PG, P4, DHEA, and E2 were dysregulated in the plasma and placenta of PE patients, which was proved via in vivo and in vitro PE models. This dysregulation of steroid hormones were mediated by steroidogenic enzymes including HSD17B3 and HSD3B1. Our findings provide new insights into the correlation of steroid hormones with PE and may be contributed to develop new diagnostic and therapeutic methodology for PE.
Preeclampsia (PE) is a pregnancy-specific hypertensive syndrome that results in substantial maternal and fetal morbidities and mortalities. The exact cause of PE has not been fully demonstrated, but abnormal formation of the placenta has been considered. The placenta connects the developing fetus to the uterine wall, producing a large amount of steroid hormones to maintain pregnancy. Steroid hormones have been widely studied in PE serum. However, steroidogenesis by steoroidogenic enzymes in the placenta of PE has not well been established. In this study, we compared concentrations of steroid hormones in PE patients, in vivo PE models and in vitro PE models. Therefore, we first analyzed the mechanism and function of steroid hormones in PE patients. Pregnenolone (PG), progesterone (P4), dehydroepiandrosterone (DHEA), and estrogen (E2) concentrations tended to decrease in PE serum and placenta, and the results were significant for P4 and E2 in the serum of PE patients. Quantification of genes related with steroidogenesis in the placenta was examined, and expression of P4- and E2-synthesizing enzymes, testosterone 17‑β‑dehydrogenase 3 (HSD17B3) and 3 β‑hydroxysteroid dehydrogenase/δ5 4‑isomerase type 1 (HSD3B1), was reduced in PE placenta compared with normal placenta. Interestingly, aromatase (CYP19A1), an enzyme critical for production of E2, was up-regulated in PE placenta, suggesting steroidogenic enzymes are dynamically regulated and could affect symptoms of PE. We next examined the concentration of steroid hormone in vivo PE rat models. The rats were treated with N-Nitro-L-arginine methyl esterhydrocholride (L-NAME) and catechol-O-methyltransferase inhibitor (COMT-I) or underwent reduced uterine perfusion pressure (RUPP) operation. Serum and placenta were extracted to investigate relationship between PE and steroid hormones after the rats were sacrificed on GD 18. L-NAME, COMT-I, and RUPP groups showed PE-like symptoms, as previously studied. COMT-I increased the level of PG and DHEA in serum, while there was no effect on the placenta. L-NAME decreased the level of PG in serum and P4 in placenta. These results suggest that abnormal regulation of steroid hormones including PG, DHEA, P4 and E2 may be affected by PE conditions. To evaluate the regulatory mechanism in placenta cells, the production of steroid hormones through steroidogenesis was determined in human placental BeWo cells treated with L-NAME and COMT-I, or exposed to hypoxia. The in vitro PE models showed similar regulation of steroid hormones with PE patients by reducing production of E2 and P4. In addition, strongly decreased level of PG and DHEA was shown. These results suggest that the decrease of E2 and P4 in PE was because of reduction of their precursor hormones such as PG and DHEA from placenta, which was mediated via regulation of expression of steroidogenic enzymes including HSD17B3 and HSD3B1. Taken together, we found that steroid hormones such as PG, P4, DHEA, and E2 were dysregulated in the plasma and placenta of PE patients, which was proved via in vivo and in vitro PE models. This dysregulation of steroid hormones were mediated by steroidogenic enzymes including HSD17B3 and HSD3B1. Our findings provide new insights into the correlation of steroid hormones with PE and may be contributed to develop new diagnostic and therapeutic methodology for PE.
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