Abstract 163: Cell-Surface Protein Disulfide Isomerase Shapes Vascular Architecture to Counteract Inward Remodeling

Abstract

BACKGROUND: Vascular remodeling orchestrates a complex network of signaling pathways responsible for pathological changes in many vascular diseases such as atherosclerosis. We investigated the role of endoplasmic reticulum chaperone Protein Disulfide Isomerase(PDI) and cell-surface PDI (ecPDI) pool in vascular caliber and architecture during vascular repair after injury(AI). Methods and Results: After rabbit iliac artery balloon injury, there was marked increase in PDI mRNA and protein (25-fold vs. basal at day 14AI), with increase in both intracellular and ecPDI. Silencing PDI by siRNA (organ culture) induced ER stress augmentation and apoptosis). PDI knockdown also upregulated proliferation marker PCNA and decreased differentiation marker calponin-C. EcPDI neutralization in vivo with PDIAb-containing perivascular gel from days 12-14AI promoted ca.25% decrease in vascular caliber at arteriography and similar decreases in total vessel circumference at optical coherence tomography, without changing neointima, indicating increased constrictive remodeling. EcPDI neutralization promoted marked changes in collagen and cytoskeleton architecture, with inverted fiber orientation and induction of thicker collagen fibrils. Collagen type I and III were decreased after ecPDI inhibition in arteries 14 days AI. Furthermore, ecPDI inhibition prevents injury-increased hydrogen peroxide generation and decreases arterial nitrate (NO3-) levels. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling. There was decreased PDI expression in media and intima from plaques exhibiting inward remodeling and, conversely, enhanced PDI expression in media of plaques exhibiting outward remodeling. CONCLUSIONS: Thus, strongly-expressed PDI after injury reshapes matrix and cytoskeleton architecture to support an anticonstrictive remodeling effect. Such findings suggest an important role for PDI in lumen maintenance during vascular remodeling.