title: Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect.
abstract: Whole-vessel remodeling critically determines lumen caliber in vascular (patho)physiology, and it is reportedly redox-dependent. We hypothesized that the cell-surface pool of the endoplasmic reticulum redox chaperone protein disulfide isomerase-A1 (peri/epicellular=pecPDI), which is known to support thrombosis, also regulates disease-associated vascular architecture. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling and plaque stability. In a rabbit iliac artery overdistension model, there was unusually high PDI upregulation (≈25-fold versus basal, 14 days postinjury), involving both intracellular and pecPDI. PecPDI neutralization with distinct anti-PDI antibodies did not enhance endoplasmic reticulum stress or apoptosis. In vivo pecPDI neutralization with PDI antibody-containing perivascular gel from days 12 to 14 post injury promoted 25% decrease in the maximally dilated arteriographic vascular caliber. There was corresponding whole-vessel circumference loss using optical coherence tomography without change in neointima, which indicates constrictive remodeling. This was accompanied by decreased hydrogen peroxide generation. Constrictive remodeling was corroborated by marked changes in collagen organization, that is, switching from circumferential to radial fiber orientation and to a more rigid fiber type. The cytoskeleton architecture was also disrupted; there was a loss of stress fiber coherent organization and a switch from thin to medium thickness actin fibers, all leading to impaired viscoelastic ductility. Total and PDI-associated expressions of β1-integrin, and levels of reduced cell-surface β1-integrin, were diminished after PDI antibody treatment, implicating β1-integrin as a likely pecPDI target during vessel repair. Indeed, focal adhesion kinase phosphorylation, a downstream β1-integrin effector, was decreased by PDI antibody. Thus, the upregulated pecPDI pool tunes matrix/cytoskeleton reshaping to counteract inward remodeling in vascular pathophysiology.
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Leonardo Y
authors.initials: LY
authors.lastname: Tanaka
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Haniel A
authors.initials: HA
authors.lastname: Araújo
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Gustavo K
authors.initials: GK
authors.lastname: Hironaka
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Thaís L S
authors.initials: TL
authors.lastname: Araujo
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Celso K
authors.initials: CK
authors.lastname: Takimura
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Andres I
authors.initials: AI
authors.lastname: Rodriguez
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Annelise S
authors.initials: AS
authors.lastname: Casagrande
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Gutierrez
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Pedro Alves
authors.initials: PA
authors.lastname: Lemos-Neto
authors.affiliation: From the Vascular Biology Laboratory (L.Y.T., H.A.A., G.K.H., T.L.S.A., A.I.R., A.S.C., F.R.M.L.), Interventional Cardiology Unit (C.K.T., P.A.L.-N.), and Pathology Laboratory (P.S.G.), Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil. francisco.laurindo@incor.usp.br.
authors.forename: Francisco R M
authors.initials: FR
authors.lastname: Laurindo
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D023921:Coronary Stenosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D008297:Male; D010766:Phosphorylation; D019704:Protein Disulfide-Isomerases / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D011817:Rabbits; D066253:Vascular Remodeling
chemical_list: D012313:RNA; D019704:Protein Disulfide-Isomerases
keywords: cytoskeleton; endoplasmic reticulum; hydrogen peroxide; protein disulfide isomerase; vascular remodeling