title: Downregulation of L-type Ca2+ channel in rat mesenteric arteries leads to loss of smooth muscle contractile phenotype and inward hypertrophic remodeling.
abstract: L-type Ca(2+) channels (LTCCs) are important for vascular smooth muscle cell (VSMC) contraction, as well as VSMC differentiation, as indicated by loss of LTCCs during VSMC dedifferentiation. However, it is not clear whether loss of LTCCs is a primary event underlying phenotypic modulation or whether loss of LTCCs has significance for vascular structure. We used small interference RNA (siRNA) transfection in vivo to investigate the role of LTCCs in VSMC phenotypic expression and structure of rat mesenteric arteries. siRNA reduced LTCC mRNA and protein expression in rat mesenteric arteries 3 days after siRNA transfection to 12.7 ± 0.7% and 47.3 ± 13%, respectively: this was associated with an increased resting intracellular Ca(2+) concentration ([Ca(2+)]i). Despite the high [Ca(2+)]i, the contractility was reduced (tension development to norepinephrine was 3.5 ± 0.2 N/m and 0.8 ± 0.2 N/m for sham-transfected and downregulated arteries respectively; P < 0.05). Expression of contractile phenotype marker genes was reduced in arteries downregulated for LTCCs. Phenotypic changes were associated with a 45% increase in number of VSMCs and a consequent increase of media thickness and media area. Ten days after siRNA transfection arterial structure was again normalized. The contractile responses of LTCC-siRNA transfected arteries were elevated in comparison with matched controls 10 days after transfection. The study provides strong evidence for causal relationships between LTCC expression and VSMC contractile phenotype, as well as novel data addressing the complex relationship between VSMC contractility, phenotype, and vascular structure. These findings are relevant for understanding diseases, associated with phenotype changes of VSMC and vascular remodeling, such as atherosclerosis and hypertension.
authors.affiliation: Department of Biomedicine, Membranes, Aarhus University, Aarhus C, Denmark; and.
authors.forename: Olga
authors.initials: O
authors.lastname: Kudryavtseva
authors.forename: Kate Møller
authors.initials: KM
authors.lastname: Herum
authors.forename: Vibeke Secher
authors.initials: VS
authors.lastname: Dam
authors.forename: Marthe Simonsen
authors.initials: MS
authors.lastname: Straarup
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kamaev
authors.forename: Donna M
authors.initials: DM
authors.lastname: Briggs Boedtkjer
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Matchkov
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjær
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006984:Hypertrophy / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009119:Muscle Contraction; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D002118:Calcium
keywords: Ca2+ signaling; vascular remodeling; voltage-dependent Ca2+ channel