title: Collectivization of Vascular Smooth Muscle Cells via TGF-β-Cadherin-11-Dependent Adhesive Switching.
abstract: OBJECTIVE
  Smooth muscle cells (SMCs) in healthy arteries are arranged as a collective. However, in diseased arteries, SMCs commonly exist as individual cells, unconnected to each other. The purpose of this study was to elucidate the events that enable individualized SMCs to enter into a stable and interacting cell collective.
  
  
  RESULTS
  Human SMCs stimulated to undergo programmed collectivization were tracked by time-lapse microscopy. We uncovered a switch in the behavior of contacting SMCs from semiautonomous motility to cell-cell adherence. Central to the cell-adherent phenotype was the formation of uniquely elongated adherens junctions, up to 60 μm in length, which appeared to strap adjacent SMCs to each other. Remarkably, these junctions contained both N-cadherin and cadherin-11. Ground-state depletion super-resolution microscopy revealed that these hybrid assemblies were comprised of 2 parallel nanotracks of each cadherin, separated by 50 nm. Blocking either N-cadherin or cadherin-11 inhibited collectivization. Cell-cell adhesion and adherens junction elongation were associated with reduced transforming growth factor-β signaling, and exogenous transforming growth factor-β1 suppressed junction elongation via the noncanonical p38 pathway. Imaging of fura-2-loaded SMCs revealed that SMC assemblies displayed coordinated calcium oscillations and cell-cell transmission of calcium waves which, together with increased connexin 43-containing junctions, depended on cadherin-11 and N-cadherin function.
  
  
  CONCLUSIONS
  SMCs can self-organize, structurally and functionally, via transforming growth factor-β-p38-dependent adhesive switching and a novel adherens junction architecture comprised of hybrid nanotracks of cadherin-11 and N-cadherin. The findings define a mechanism for the assembly of SMCs into networks, a process that may be relevant to the stability and function of blood vessels.
authors.affiliation: From the Robarts Research Institute (B.B., H.Y., J.G.P.), Departments of Medicine (Cardiology) (J.G.P.), Biochemistry (J.G.P.), Medical Biophysics (B.B., J.G.P.), Pathology and Laboratory Medicine (S.C.), Surgery (M.W.A.C.), and Physiology and Pharmacology (S.M.S.), University of Western Ontario, London Health Sciences Centre (S.C., J.G.P.), London, Ontario, Canada.
authors.forename: Brittany
authors.initials: B
authors.lastname: Balint
authors.affiliation: From the Robarts Research Institute (B.B., H.Y., J.G.P.), Departments of Medicine (Cardiology) (J.G.P.), Biochemistry (J.G.P.), Medical Biophysics (B.B., J.G.P.), Pathology and Laboratory Medicine (S.C.), Surgery (M.W.A.C.), and Physiology and Pharmacology (S.M.S.), University of Western Ontario, London Health Sciences Centre (S.C., J.G.P.), London, Ontario, Canada.
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.affiliation: From the Robarts Research Institute (B.B., H.Y., J.G.P.), Departments of Medicine (Cardiology) (J.G.P.), Biochemistry (J.G.P.), Medical Biophysics (B.B., J.G.P.), Pathology and Laboratory Medicine (S.C.), Surgery (M.W.A.C.), and Physiology and Pharmacology (S.M.S.), University of Western Ontario, London Health Sciences Centre (S.C., J.G.P.), London, Ontario, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: From the Robarts Research Institute (B.B., H.Y., J.G.P.), Departments of Medicine (Cardiology) (J.G.P.), Biochemistry (J.G.P.), Medical Biophysics (B.B., J.G.P.), Pathology and Laboratory Medicine (S.C.), Surgery (M.W.A.C.), and Physiology and Pharmacology (S.M.S.), University of Western Ontario, London Health Sciences Centre (S.C., J.G.P.), London, Ontario, Canada.
authors.forename: Michael W A
authors.initials: MW
authors.lastname: Chu
authors.affiliation: From the Robarts Research Institute (B.B., H.Y., J.G.P.), Departments of Medicine (Cardiology) (J.G.P.), Biochemistry (J.G.P.), Medical Biophysics (B.B., J.G.P.), Pathology and Laboratory Medicine (S.C.), Surgery (M.W.A.C.), and Physiology and Pharmacology (S.M.S.), University of Western Ontario, London Health Sciences Centre (S.C., J.G.P.), London, Ontario, Canada.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sims
authors.affiliation: From the Robarts Research Institute (B.B., H.Y., J.G.P.), Departments of Medicine (Cardiology) (J.G.P.), Biochemistry (J.G.P.), Medical Biophysics (B.B., J.G.P.), Pathology and Laboratory Medicine (S.C.), Surgery (M.W.A.C.), and Physiology and Pharmacology (S.M.S.), University of Western Ontario, London Health Sciences Centre (S.C., J.G.P.), London, Ontario, Canada. gpickering@robarts.ca.
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D012016:Reference Values; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D053773:Transforming Growth Factor beta1; C086960:osteoblast cadherin
keywords: adhesion molecules; cadherin 11; cell; myocytes, smooth muscle