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...

INTRODUCTION: 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 the extracellular PDI (ecPDI) pool in vascular caliber and architecture during vascular repair and remodeling after injury (AI). METHODS AND RESULTS: After rabbit iliac artery balloon injury, PDI is markedly increased at mRNA and protein levels (25-fold vs. basal 14 days AI), with increase in both intracellular and ecPDI. Silencing PDI by siRNA in vitro induced ER stress markers upregulation and apoptosis (assessed by TUNEL assay). PDI knockdown also upregulated proliferation marker PCNA and decreased differentiation marker calponin-C. Furthermore, ecPDI inhibition prevents injury-increased hydrogen peroxide generation and decreases arterial nitrate (NO3-) level. EcPDI neutralization in vivo with PDIAb-containing perivascular gel from days 12-14AI promoted 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 striking changes in collagen, with switch from circumferential to radial fiber orientation towards a more rigid fiber type. Collagen type I and III were decreased after ecPDI inhibition in arteries 14 days AI. Cytoskeleton architecture was also disrupted, with loss of stress fiber coherent organization and switch from thin to medium-thickness actin fibers. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling. There was decreased PDI expression in media and intima from plaques exhibiting constrictive remodeling and, conversely, enhanced PDI expression in media of plaques depicting outward remodeling. CONCLUSIONS: Thus, PDI is highly upregulated after injury and 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.

Endoplasmic reticulum(ER) redox chaperone protein disulfide isomerase(PDI) regulates vascular/phagocytic NADPH oxidase and supports cell migration. We investigated the role of PDI during vascular repair after injury(AI) induced by balloon in rabbit iliac artery. There was marked increase of PDI mRNA and protein(5–10‐fold) at 4, 7 and 14 days AI vs. intact control(CT). PDI immunostaining was greater in intima = neo‐endothelium > media. Increased cell‐surface PDI was also evident. ER stress‐related KDEL chaperones also increased with similar time‐course AI. PDI siRNA(siPDI) transfection in cultured vessel rings collected 14 days AI enhanced KDEL expression vs. scrambled siRNA(siScr) (siScr 2.1±0.9 vs. siPDI 5.0±2.3‐fold vs. CT, p<0.05), apoptosis (siScr 4.6±0.2 vs. siPDI 6.2±0.9 %TUNEL + nuclei, p<0.05) and proliferation marker PCNA (siScr 1.2±0.3 vs. siPDI 4.0 ±0.2 AU, p<0.05), and decreased differentiation marker calponin‐C (siScr 0.52±0.04 vs. siPDI 0.36 ±0.04 AU, p<0.05). siPDI in CT rings did not alter such variables. PCR array analysis showed analogous pattern of mRNA changes. Also, siPDI 14 days AI upregulated Nox1 and downregulated Nox4 NADPH oxidase, while siPDI attenuated oxidant production (in situ hydroethidine) only in CT vessels. Thus, strongly‐overexpressed PDI 14 days AI protects against apoptosis and ER stress and sustains VSMC differentiation. Support: FAPESP, CNPq/INCT Redoxoma

A 75-year-old man sought medical assistance due to hemoptysis and general malaise. The patient presented dyspnea triggered by moderate exertion at the end of April. A week after the symptom onset, the dyspnea increased and started to be triggered by mild exertion. He also suffered a syncopal episode, which prompted him to seek emergency medical attention.Two weeks later he sought medical assistance at Instituto do Coracao (InCor -The Heart Institute) due to worsening of the dyspnea and a sensation of suffocation in the chest.The physical examination (May 10, 2008) showed a heart rate (HR) of 88 bpm and blood pressure (BP) of 90/60 mm Hg. The lung examination disclosed pulmonary rales. The remainder of the examination did not reveal any other alterations.The electrocardiogram (May 10, 2008) showed sinus rhythm; HR at 88 bpm; PR interval of 203 ms; QRS duration of 68 ms; low-voltage QRS complex in the frontal plane; extensive anterior and inferior-wall areas that were electrically inactive; and ST-segment elevation from V 1 to V 6 and in I aVL, with positive T waves from V 1 to V 6 (Figure 1).The laboratory assessment (May 10, 2008) showed glycemia of 94 mg/dl; urea of 43 mg/dl; creatinine of 1.07 mg/dl; sodium of 137 mEq/l; potassium of 4.5 mEq/l; hemoglobin of 12.6 g/dl; leukocytes at 6,500/mm³; platelets at 286,000/m³; INR of 1.1; APTT (patient/control ratio) of 1.12; CKMB of 6.46 ng/ml and troponin of 6.27 ng/ml.The chest X-ray (05. 10. 2008) showed cardiomegaly at the expense of the left ventricle (LV).The echocardiogram (05. 14. 2008) showed an enlarged left atrium (45 mm). The left ventricular ejection fraction (LVEF) was 20%. Akinesis of the LV septal and anterior segments and signs suggestive of intracavitary thrombi in the apical region, one measuring 2.4 x 5 mm, fixed, and a mobile one in middle septal segment measuring 1.0 x 0.7 mm, were diagnosed. There was slight pericardial effusion. The pulmonary artery pressure was estimated at 30 mmHg.The coronary angiography (May 14, 2008) identified occlusion of the anterior interventricular branch of the left coronary artery, a 90% lesion at the emergence of the first diagonal branch and a 70% in the left marginal branch; there were also irregularities in the right coronary artery. An angioplasty of the anterior interventricular branch was attempted; however, the guidewire did not surpass the lesion and an angioplasty in the first diagonal branch was performed with a balloon-catheter.The patient was discharged from the hospital (May 20, 2008) with a daily prescription of 100 mg ASA, 12.5 mg carvedilol, 10 mg enalapril, 25 mg spironolactone, 20 mg simvastatin and 5 mg warfarin .The patient developed dyspnea triggered by moderate exertion and three days later, stated to present dyspnea even at rest. On the morning of the following day, he presented an episode of precordial discomfort, followed by intense sudoresis and nausea that lasted for 30 minutes. He sought medical attention at InCor seven hours after the pain onset.At physical examination (May 24, 200...

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