BACKGROUND: Females with slow transit constipation (STC) exhibit progesterone receptor (P4R) overexpression in colon muscle that impair their contractility. These studies examined whether these patients have an overexpression of P4R in epithelial cells and whether P4 affects the SERT-5-HT pathway. METHODS: Tissues were obtained from surgical specimens of seven females with STC and six controls. Feasibility studies were performed in biopsies from six patients with STC and three controls. P4R, SERT and TPH-1 mRNA and protein expression and 5-HT by ELISA were determined. Contraction was studied in normal muscle cells pretreated with P4 or buffer. Progesterone effects on SERT and 5-HT levels were studied in normal human mucosa in vitro and in wild and SERT knockout mice in vivo. KEY RESULTS: P4R was overexpressed in epithelial cells in STC compared with controls. The levels of SERT were lower and 5-HT higher in STC. In epithelial cells P4 treatment decreased SERT and increased mucosal 5-HT without affecting TPH-1. Progesterone impaired the contraction of normal muscle cells induced by Ach and 5-HT. Progesterone decreased SERT and increased 5-HT levels in the colon of wild mice in vivo but had no effect on the high basal levels of 5-HT in SERT knockout mice. CONCLUSIONS & INFERENCES: P4R are present in colon epithelial cells and are overexpressed in females with STC. These cells have reduced SERT and high 5-HT levels and normal TPH-1. These 5-HT signaling abnormalities are related to overexpression of P4R since they are reproduced in human epithelial cells in vitro and in mice in vivo.
BACKGROUND: Females with slow transit constipation (STC) exhibit progesterone receptor (P4R) overexpression in colon muscle that impair their contractility. These studies examined whether these patients have an overexpression of P4R in epithelial cells and whether P4 affects the SERT-5-HT pathway. METHODS: Tissues were obtained from surgical specimens of seven females with STC and six controls. Feasibility studies were performed in biopsies from six patients with STC and three controls. P4R, SERT and TPH-1 mRNA and protein expression and 5-HT by ELISA were determined. Contraction was studied in normal muscle cells pretreated with P4 or buffer. Progesterone effects on SERT and 5-HT levels were studied in normal human mucosa in vitro and in wild and SERT knockout mice in vivo. KEY RESULTS: P4R was overexpressed in epithelial cells in STC compared with controls. The levels of SERT were lower and 5-HT higher in STC. In epithelial cells P4 treatment decreased SERT and increased mucosal 5-HT without affecting TPH-1. Progesterone impaired the contraction of normal muscle cells induced by Ach and 5-HT. Progesterone decreased SERT and increased 5-HT levels in the colon of wild mice in vivo but had no effect on the high basal levels of 5-HT in SERT knockout mice. CONCLUSIONS & INFERENCES: P4R are present in colon epithelial cells and are overexpressed in females with STC. These cells have reduced SERT and high 5-HT levels and normal TPH-1. These 5-HT signaling abnormalities are related to overexpression of P4R since they are reproduced in human epithelial cells in vitro and in mice in vivo.
Authors: Paola Iovino; Giuseppe Chiarioni; Giancarlo Bilancio; Massimo Cirillo; Igor B Mekjavic; Rado Pisot; Carolina Ciacci Journal: PLoS One Date: 2013-08-20 Impact factor: 3.240