title: Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses.
abstract: Elevated levels of serotonin (5-HT) and endothelin-1 (ET-1) may be involved in cardiovascular complications of diabetes mellitus. Data suggest supraphysiological concentrations of 5-HT (10(-6) M) potentiate the ability of ET-1 to stimulate DNA synthesis and vascular smooth muscle cell (VSMC) proliferation in vitro via activation of mitogen-activated protein kinase (p42/44 MAPK) and Janus kinase 2 (JAK2) pathways. Additionally, 5-HT enhances agonist-induced contractions via p42/44 MAPK and an unknown tyrosine kinase. However, the exact mechanisms of the 5-HT/ET-1 interactions and whether these effects occur at physiological levels (10(-9) M) are unknown. Therefore, we hypothesized that interactions between 5-HT and ET-1 at physiological concentrations in VSMC enhanced activation of both p42/44 MAPK and JAK2 pathways contributing to vascular growth and contractile responses. With the use of rat VSMC and Western blot analysis, our data suggest no effect of acute (30 min) preincubation with 5-HT (10(-9) M) and/or ET-1 (10(-9) M) on the activation of either pathway in normal or high glucose conditions. To determine if there was altered vascular reactivity in intact vessels we tested the effects of 5-HT and ET-1 interaction using myographs to measure isometric contractions of rat thoracic aortic rings. 5-HT (10(-9) M) and ET-1 (10(-12) M) stimulate enhanced contractile responses to each other that were inhibited by JAK2 and p42/44 MAPK antagonists. Our findings demonstrate that both 5-HT and ET-1 at physiological concentrations could interact with each other and activate p42/44 MAPK and JAK2 signaling pathways to cause an increase in smooth muscle contraction that could lead to altered vascular function.
authors.affiliation: Department of Biological Sciences, Oakland University, Rochester, Michigan.
authors.forename: Subha
authors.initials: S
authors.lastname: Bhaskaran
authors.forename: Jeremy
authors.initials: J
authors.lastname: Zaluski
authors.forename: Amy
authors.initials: A
authors.lastname: Banes-Berceli
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology
chemical_list: D019332:Endothelin-1; D012701:Serotonin
keywords: Janus kinase 2 (JAK2); diabetes; endothelin-1 (ET-1); p42/44 mitogen-activated protein kinase (p42/44 MAPK); serotonin (5-HT); vascular smooth muscle cell (VSMC)