title: Inhibition of protein tyrosine phosphatases unmasks vasoconstriction and potentiates calcium signaling in rat aorta smooth muscle cells in response to an agonist of 5-HT2B receptors BW723C86.
abstract: In blood vessels, serotonin 5-HT2B receptors mainly mediate relaxation, although their activation by the selective agonist BW723C86 is known to exert contraction of aorta in deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-l-arginine (l-NAME) hypertensive rats [Russel et al., 2002; Banes et al., 2003] and in mice with type 2 diabetes [Nelson et al., 2012]. The unmasking effect on vasoconstriction can be caused by a shift in the balance of tyrosine phosphorylation in smooth muscle cells (SMC) due to oxidative stress induced inhibition of protein tyrosine phosphatases (PTP). We have demonstrated that BW723C86 which does not cause contraction of rat aorta and mesenteric artery rings, evoked a vasoconstrictor effect in the presence of PTP inhibitors sodium orthovanadate (Na3VO4) or BVT948. BW723C86 induced a weak rise of [Ca2+]iin the SMC isolated from rat aorta; however, after pre-incubation with Na3VO4the response to BW723C86 increased more than 5-fold. This effect was diminished by protein tyrosine kinase (PTK) inhibitor genistein, inhibitor of Src-family kinases PP2, inhibitor of NADPH-oxidase VAS2870 and completely suppressed by N-acetylcysteine and 5-HT2B receptor antagonist RS127445. Using fluorescent probe DCFH-DA we have shown that Na3VO4induces oxidative stress in SMC. In the presence of Na3VO4BW723C86 considerably increased formation of reactive oxygen species while alone had no appreciable effect on DCFH oxidation. We suggest that oxidative stress causes inhibition of PTP and unmasking of 5-HT2B receptors functional activity.
authors.affiliation: Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Galina Y
authors.initials: GY
authors.lastname: Mironova
authors.affiliation: Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Piotr P
authors.initials: PP
authors.lastname: Avdonin
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Goncharov
authors.affiliation: School of Allied Health Sciences, De Montfort University, Leicester, UK.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Jenkins
authors.affiliation: Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia. Electronic address: pvavdonin@yandex.ru.
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Avdonin
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects*; D002469:Cell Separation; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress; D017027:Protein Tyrosine Phosphatases / Q000032:analysis*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014638:Vanadates / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; D007211:Indoles; D012333:RNA, Messenger; D044403:Receptor, Serotonin, 5-HT2B; D058826:Serotonin 5-HT2 Receptor Agonists; D013876:Thiophenes; D014662:Vasoconstrictor Agents; D014638:Vanadates; D017027:Protein Tyrosine Phosphatases
keywords: 5-HT2B receptors; Calcium; Hypertension; Oxidative stress; Protein tyrosine phosphatases; Smooth muscle cells