Protein disulfide isomerase regulates blood vessel caliber in vascular disease

Redoxoma Highlights by Francisco R. M. Laurindo

While the intuitive idea is that the lumen of diseased blood vessels narrows due to the pathological growth of a migrating cell mass, similar to rust in an old pipe, actually the lumen of diseased vessels is strongly influenced by a phenomenon called vascular remodeling, the structural reorganization of whole-vessel circumference. Typically, remodeling is the sole determinant of vessel lumen due to blood flow changes, in which redox signaling processes play an important mediator role in association with NO biovailability. However, redox processes appear to mediate other forms of vascular remodeling as well, such as those associated with atherosclerosis-related processes. We showed previously that superoxide dismutase underexpression supports vasoconstrictive remodeling during vascular repair after injury, so that replenishment of extracelular SOD (SOD3) partially prevented such caliber loss and enhanced NO biovailability [1]. However, the mechanisms that organize and orchestrate such redox-dependent pathways are unclear. Recent work from our group provided evidence that the extracellular pool of the endoplasmic reticulum (ER) redox chaperone protein disulfide isomerase (PDIA1 or PDI), known to play important roles in redox homeostasis and signaling, may counteract constrictive remodeling [2]. We termed such extracellular PDI pool "pecPDI", as it comprises cell-surface(epicellular) and secreted (peri-cellular) fractions. PecPDI is well-known to redox-regulated processes such as intravascular thrombosis and platelet activation, viral infection and integrin-mediated cell adhesion. We first assessed PDI immunoreactivity in autopsy atheroma specimens from patients dying from acute coronary events. Results showed decreased PDI immunoreactivity in plaques exhibiting constrictive remodeling and, in parallel, enhanced PDI expression in plaques exhibiting expansive remodeling. These findings led us to further investigate PDI and specifically pecPDI modulation of vascular remodeling in the model of vascular repair post-injury in experimental models. In rabbits submitted to balloon angioplasty-like iliac artery injury, PDIA1 expression was massively enhanced at 14 days post-injury (25-fold vs. baseline), while pecPDI pool exhibited a parallel increase. Neutralization of pecPDI with 2 distinct antibodies delivered in pluronic gel at the perivascular injury site promoted significant decreases in vessel lumen caliber. In parallel, in vivo experiments with optical coherence tomography, as well as histological analysis not only confirmed such lumen loss, but showed that it was due not to vascular cell overgrowth but rather to vasoconstrictive remodeling. That is, pecPDI neutralization promoted decrease in whole vessel circumference without increased neointima mass. The occurrence of such constrictive remodeling was confirmed through marked changes in collagen structural organization, as well as actin cytoskeleton disorganization. Integrin beta1 was identified as a redox-modulated target of pecPDI, indicating a possible transmembrane mechanism through which pecPDI-induced redox changes can promote reorganization of intracellular cytoskeleton and extracellular matrix. Additional experimentss suggested that pecPDI is implicated in the reductive modification of cell surface thiols, which is the probable mechanism by which it activates integrins. Importantly, we also showed that pecPDI neutralization impairs actin stress fiber remodeling in cultured cells submitted to mechanostimuli (stretch or shear stress). Thus, pecPDI effects associates with redox-dependent mechanisms supporting vascular expansive remodeling and lumen preservation (that is, an anti-constrictive remodeling effect). Moreover, pecPDI may be a novel mediator of mechanoadaptation in vascular cells. These results may have pathophysiological implications to understand and potentially remediate vascular disease [3].

1. P. F. Leite, A. Danilovic, P. Moriel, K. Dantas, S. Marklund, A. P. Dantas, F. R. Laurindo. Sustained decrease in superoxide dismutase activity underlies constrictive Remodeling after balloon injury in rabbits. Arteriosclerosis, Thrombosis, and Vascular Biology, 23: 2197-202, 2003 | doi: 10.1161/01.atv.0000093980.46838.41
2. L. Y. Tanaka, H. A. Araújo, G. K. Hironaka, T. L. S. Araujo, C. K. Takimura, A. I. Rodriguez, A. S. Casagrande, P. S. Gutierrez, P. A. Lemos-Neto, F. R. Laurindo. Peri/epicellular protein disulfide isomerase sustains vascular lumen caliber through an anti-constrictive remodeling effect. Hypertension, 67: 613-22, 2016 | doi: 10.1161/hyperten1sionaha.115.06177
3. E. Schulz, T. Münzel. Lumen Size Matters: Role of Protein Disulfide Isomerase A1 in Vascular Remodeling. Hypertension, 67(3): 488-9, 2016 | doi: 10.1161/hypertensionaha.115.06296