title: Procontractile G protein-mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling.
abstract: Vascular smooth muscle (Sm) cells (VSMCs) are highly plastic. Their differentiation state can be regulated by serum response factor (SRF), which activates genes involved in Sm differentiation and proliferation by recruiting cofactors, such as members of the myocardin family and ternary complex factors (TCFs), respectively. However, the extracellular cues and upstream signaling mechanisms regulating SRF-dependent VSMC differentiation under in vivo conditions are poorly understood. In this study, we show that the procontractile signaling pathways mediated by the G proteins G(12)/G(13) and G(q)/G(11) antagonistically regulate VSMC plasticity in different models of vascular remodeling. In mice lacking Gα(12)/Gα(13) or their effector, the RhoGEF protein LARG, RhoA-dependent SRF-regulation was blocked and down-regulation of VSMC differentiation marker genes was enhanced. This was accompanied by an excessive vascular remodeling and exacerbation of atherosclerosis. In contrast, Sm-specific Gα(q)/Gα(11) deficiency blocked activation of extracellular signal-regulated kinase 1/2 and the TCF Elk-1, resulting in a reduced VSMC dedifferentiation in response to flow cessation or vascular injury. These data show that the balanced activity of both G protein-mediated pathways in VSMCs is required for an appropriate vessel remodeling response in vascular diseases and suggest new approaches to modulate Sm differentiation in vascular pathologies.
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Till F
authors.initials: TF
authors.lastname: Althoff
authors.forename: Julián
authors.initials: J
authors.lastname: Albarrán Juárez
authors.forename: Kerstin
authors.initials: K
authors.lastname: Troidl
authors.forename: Cong
authors.initials: C
authors.lastname: Tang
authors.forename: Shengpeng
authors.initials: S
authors.lastname: Wang
authors.forename: Angela
authors.initials: A
authors.lastname: Wirth
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001794:Blood Pressure; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D064067:Rho Guanine Nucleotide Exchange Factors; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013686:Telemetry
chemical_list: D001057:Apolipoproteins E; C577223:Arhgef12 protein, mouse; D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D026362:Serum Response Factor; D019204:GTP-Binding Proteins