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

Abstract

V ascular remodeling involves changes for the whole-vessel circumference and crucially determines lumen caliber 1 in physio(patho)logical situations, such as shear-stress responses, restenosis postangioplasty, 1-3 or native atherosclerosis. 1,4 Moreover, cellular mechanisms governing conductance vessel remodeling are likely shared by small-vessel remodeling, for example, in hypertension.5 Despite such relevance, mechanisms of vessel remodeling are not well known. The identification of endothelium 6 and nitric oxide 7 dependency of shear-induced remodeling raised possible mediator roles of redox processes, as indeed supported by many subsequent studies. 3,8 We showed previously that superoxide dismutase underactivity favors constrictive remodeling after injury (AI), whereas exogenous replenishment of SOD3(ecSOD) rescued bioactive nitric oxide from inducible NO synthase and normalized vessel caliber by counteracting constrictive remodeling rather than neointimal growth. 3 The randomized clinical trial Multivitamins and Probucol Study showed that the antioxidant probucol significantly prevented restenosis postballoon angioplasty, essentially by preventing constrictive remodeling rather than neointima formation. 9Such redox-responsiveness is in line with the importance of redox pathways in cytoskeletal dynamics 10 and extracellular matrix organization, 11 which are both crucially involved in vessel remodeling. However, molecular determinants of such redox signaling pathways remain unclear.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 antibodycontaining 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...

Golgi-independent routes support protein disulfide isomerase externalization in vascular smooth muscle cells

“…We had previously shown that csPDI is detectable in rabbit aorta segments in this condition [15]. However, given the lack of detectable soluble PDI secretion in cultured VSMC (Fig.…”

“…Moreover, little is known about pecPDI in vascular smooth muscle cells (VSMC). We previously reported that pecPDI exerts an anti-constrictive vascular remodeling effect during post-injury vessel repair in association with extracellular matrix and cytoskeleton reorganization in EC and VSMC, together with β1integrin thiol reduction [15]. Also, pecPDI neutralization in VSMC stimulates procoagulant microparticle release in P2rx7 –/– mice [23].…”

“…Some pecPDI-associated functions include: a) disulfide bond reduction of HIV glycoprotein gp120, tumor endothelial marker-5, αvβ3 integrins, tissue factor, αMβ2 and β1 integrin [6]; b) dithiol oxidation of alpha5 integrin [8] and c) thiol-disulfide isomerization of ADAM17 and αIIbβ3 [6]. Such effects associate with pecPDI-mediated regulation of viral infection [9], [10], platelet activation [11], [12], thrombosis [7], [13], [14] and expansive vascular remodeling [15]. PecPDI inhibition is increasingly investigated as a novel promising anti-thrombotic strategy [16], through cell-impermeable compounds that target PDI b'x or b' substrate-binding domains [17], [18], while targetting of the redox-active a' domain also has an attractive anti-thrombotic potential [19], [20].…”

Modularidade gênica das famílias da dissulfeto isomerase proteica e do inibidor da dissociação de guanina: estudos computacionais, moleculares e funcionais

“…Este fato não surpreende, uma vez que a grande maioria dos genes microssintênicos e blocos genômicos regulados em eucariotos envolve genes ligados a desenvolvimento ou transcrição gênica (Irimia et al, 2013 RhoGDIα na camada íntima de vasos submetidos a remodelamento mediado por fluxo é consistente com os efeitos de PDIA1 observados previamente em nosso grupo. Estes incluem a migração e organização do citoesqueleto celular (Pescatore et al, 2012), bem como remodelamento vascular durante reparação à lesão e mecanoadaptação em resposta a estímulos biomecânicos (Tanaka et al, 2016). Os efeitos da PDIA1 na regulação do citoesqueleto celular parecem extrapolar o papel dessa PDI na regulação do complexo Nox NADPH oxidase, bastante estudado por nosso grupo e per se um sistema regulador do citoesqueleto (Moretti e Laurindo, 2016).…”

“…Estas observações vão ao encontro de vários outros resultados de nosso grupo indicando que PDIA1 exerce importante regulação da arquitetura do citoesqueleto (Pescatore et al, 2012; Moretti e Laurindo -em revisão) e do remodelamento vascular (Tanaka et al, 2016). Em conjunto, estes resultados reforçam significativamente a convergência funcional entre RhoGDIs e membros da família das PDIs, com implicações funcionais na organização do citoesqueleto e morfologia celular.…”