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

Author(s)

Tanaka, Leonardo Y. ^[1] ; Araujo, Haniel A. ^[1] ; Hironaka, Gustavo K. ^[1] ; Araujo, Thais L. S. ^[1] ; Takimura, Celso K. ^[2] ; Rodriguez, Andres I. ^[1] ; Casagrande, Annelise S. ^[1] ; Gutierrez, Paulo S. ^[3] ; Lemos-Neto, Pedro Alves ^[2] ; Laurindo, Francisco R. M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Med, Vasc Biol Lab, Heart Inst InCor, Ave Eneas C Aguiar, 44, Annex 2, 9th Floor, BR-05403000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med, Intervent Cardiol Unit, Heart Inst InCor, BR-05403000 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Med, Pathol Lab, Heart Inst InCor, BR-05403000 Sao Paulo - Brazil

• Document type: Journal article
• Source: Hypertension; v. 67, n. 3, p. 613-622, MAR 2016.
• Web of Science Citations: 13

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 (approximate to 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 1-integrin, and levels of reduced cell-surface 1-integrin, were diminished after PDI antibody treatment, implicating 1-integrin as a likely pecPDI target during vessel repair. Indeed, focal adhesion kinase phosphorylation, a downstream 1-integrin effector, was decreased by PDI antibody. Thus, the upregulated pecPDI pool tunes matrix/cytoskeleton reshaping to counteract inward remodeling in vascular pathophysiology. (AU)

• FAPESP's process: 09/54764-6 - Regulation of redox homeostasis and integrated stress response by Protein Disulfide Isomerase (PDI): mechanisms and role in the pathophysiology and therapy of vascular diseases
• Grantee: Francisco Rafael Martins Laurindo
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/06360-0 - Study of gene expression in the vascular repair response after injury : effects of protein disulfide isomerase suppression
• Grantee: Haniel Alves Araujo
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC