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Original Article

Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect

Leonardo Y. Tanaka, Haniel A. Araújo, Gustavo K. Hironaka, Thaís L.S Araujo, Celso K. Takimura, Andres I. Rodriguez, Annelise S. Casagrande, Paulo S. Gutierrez, Pedro Alves Lemos-Neto, Francisco R.M. Laurindo
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https://doi.org/10.1161/HYPERTENSIONAHA.115.06177
Hypertension. 2016;HYPERTENSIONAHA.115.06177
Originally published January 18, 2016
Leonardo Y. Tanaka
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.
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Haniel A. Araújo
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.
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Gustavo K. Hironaka
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.
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Thaís L.S Araujo
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.
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Celso K. Takimura
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.
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Andres I. Rodriguez
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.
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Annelise S. Casagrande
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.
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Paulo S. Gutierrez
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.
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Pedro Alves Lemos-Neto
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.
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Francisco R.M. Laurindo
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.
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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.

  • cytoskeleton
  • endoplasmic reticulum
  • hydrogen peroxide
  • protein disulfide isomerase
  • vascular remodeling
  • Received July 21, 2015.
  • Revision received August 3, 2015.
  • Accepted November 16, 2015.
  • © 2016 American Heart Association, Inc.
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    Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect
    Leonardo Y. Tanaka, Haniel A. Araújo, Gustavo K. Hironaka, Thaís L.S Araujo, Celso K. Takimura, Andres I. Rodriguez, Annelise S. Casagrande, Paulo S. Gutierrez, Pedro Alves Lemos-Neto and Francisco R.M. Laurindo
    Hypertension. 2016;HYPERTENSIONAHA.115.06177, originally published January 18, 2016
    https://doi.org/10.1161/HYPERTENSIONAHA.115.06177

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    Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect
    Leonardo Y. Tanaka, Haniel A. Araújo, Gustavo K. Hironaka, Thaís L.S Araujo, Celso K. Takimura, Andres I. Rodriguez, Annelise S. Casagrande, Paulo S. Gutierrez, Pedro Alves Lemos-Neto and Francisco R.M. Laurindo
    Hypertension. 2016;HYPERTENSIONAHA.115.06177, originally published January 18, 2016
    https://doi.org/10.1161/HYPERTENSIONAHA.115.06177
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