SEROTONIN REGULATION OF GENE-EXPRESSION IN UTERINE EXTRACELLULAR-MATRIX - RECIPROCAL EFFECTS ON COLLAGENS AND COLLAGENASE

The regulation of collagen gene expression by serotonin was investigat ed in rat uterine smooth muscle cells. Serotonin treatment of myometri al cells caused decreases of up to 10-fold in levels of type I collage n mRNA. Decreases in secreted type 1 collagen protein paralleled decre ases in collagen mRNA. The effective half-life of collagen mRNA in ser otonin-treated cells was approximately 1.7 days. Selective 5-HT2 recep tor agonists mimicked the effects of serotonin, while the effects of s erotonin were blocked by 5-HT2 antagonists, Nuclear run-on analysis sh owed that serotonin-dependent decreases in collagen mRNA are accompani ed by decreased transcription. Progesterone analogs, which inhibit the serotonin-dependent activation of the gene for interstitial collagena se, had no effect on the ability of serotonin to decrease collagen mRN A. Conversely, the cell-permeable cAMP analog, 8-bromo-cAMP, mimicked the effects of serotonin on type I collagen mRNA and protein. Serotoni n also decreased levels of the mRNAs for type III collagen and fibrone ctin, but had no effect on the mRNAs for type IV collagen. These resul ts indicate that serotonin, previously shown to upregulate the interst itial collagenase gene, downregulates the: gene for type I collagen an d other extracellular matrix proteins, possibly by a novel mechanism o f action downstream of 5-HT2 receptor binding.