title: Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries.
abstract: OBJECTIVE
  We have previously characterized a cGMP-dependent Ca(2+)-activated Cl(-) current in vascular smooth muscle cells (SMCs) and have shown its dependence on bestrophin-3 expression. We hypothesize that this current is important for synchronization of SMCs in the vascular wall. In the present study, we aimed to test this hypothesis by transfecting rat mesenteric small arteries in vivo with siRNA specifically targeting bestrophin-3.
  
  
  RESULTS
  The arteries were tested 3 days after transfection in vitro for isometric force development and for intracellular Ca(2+) in SMCs. Bestrophin-3 expression was significantly reduced compared with arteries transfected with mutated siRNA. mRNA levels for bestrophin-1 and -2 were also significantly reduced by bestrophin-3 down-regulation. This is suggested to be secondary to specific bestrophin-3 down-regulation since siRNAs targeting different exons of the bestrophin-3 gene had identical effects on bestrophin-1 and -2 expression. The transfection affected neither the maximal contractile response nor the sensitivity to norepinephrine and arginine-vasopressin. The amplitude of agonist-induced vasomotion was significantly reduced in arteries down-regulated for bestrophins compared with controls, and asynchronous Ca(2+) waves appeared in the SMCs. The average frequency of vasomotion was not different. 8Br-cGMP restored vasomotion in arteries where the endothelium was removed, but oscillation amplitude was still significantly less in bestrophin-down-regulated arteries. Thus, vasomotion properties were consistent with those previously characterized for rat mesenteric small arteries. Data from our mathematical model are consistent with the experimental results.
  
  
  CONCLUSIONS
  This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.
authors.affiliation: Department of Physiology and Biophysics, Aarhus University, Ole Worms Alle bygn.4, 1163, Aarhus C 8000, Denmark.
authors.forename: Torbjoern
authors.initials: T
authors.lastname: Broegger
authors.forename: Jens Christian Brings
authors.initials: JC
authors.lastname: Jacobsen
authors.forename: Vibeke
authors.initials: V
authors.lastname: Secher Dam
authors.forename: Donna M Briggs
authors.initials: DM
authors.lastname: Boedtkjer
authors.forename: Henrik
authors.initials: H
authors.lastname: Kold-Petersen
authors.forename: Finn Skou
authors.initials: FS
authors.lastname: Pedersen
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjaer
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Matchkov
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D000075002:Bestrophins; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C508904:Best1 protein, rat; C568921:Best2 protein, rat; C568920:Best3 protein, rat; D000075002:Bestrophins; D018118:Chloride Channels; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D001127:Arginine Vasopressin; D002118:Calcium; D009638:Norepinephrine