Endothelial Dysfunction and Collagen Accumulation

Lafont, Antoine; Durand, Éric; Samuel, Jane‐Lise; Besse, B.; Addad, Faouzi; Lévy, Bernard; Desnos, Michel; Guérot, C; Boulanger, Chantal

doi:10.1161/01.cir.100.10.1109

Cited by 113 publications

(45 citation statements)

References 40 publications

(35 reference statements)

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“…2,3 Diminished production of vasculoprotective mediators such as NO is a major contributory factor in this pathological process. We hypothesized that adenoviral-mediated gene transfer of NOS genes to the injured carotid artery would increase NO bioavailability within the vessel wall which in turn would enhance endothelial regeneration and inhibit intimal hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

“…2 Disruption of the endothelial layer following angioplasty procedures has also been implicated in the pathological repair of injured blood vessels. 3 Impaired endothelial function leads to reduced production of key vascular mediators such as nitric oxide (NO) resulting in increased smooth muscle cell proliferation and migration, platelet adhesion and impaired endotheliumdependant vasorelaxation (EDVR). 4 All of the above processes are significant elements in the pathological repair of the injured artery following angioplasty procedures ultimately resulting in intimal hyperplasia.…”

Section: Introductionmentioning

confidence: 99%

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Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury

et al. 2006

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Endothelial cell loss is a critical event in the pathological repair of the injured blood vessel. Impaired endothelial function results in reduced production of key vascular mediators such as nitric oxide (NO) within the vessel wall leading to enhanced smooth muscle cell proliferation and migration and ultimately intimal hyperplasia. The aim of the present study was to directly compare the effects of adenoviral-mediated gene delivery of two nitric oxide synthase (NOS) isoforms, eNOS and iNOS on endothelial regeneration and intimal hyperplasia following endothelial injury in the rabbit carotid artery. The right carotid arteries of male New Zealand white rabbits were denuded by passing a 3French Fogarty balloon catheter along the artery three times. In all, 1 Â 10 9 PFU of adenoviral(Ad)eNOS, AdiNOS or Adb-galactosidase (Adb-Gal) was then delivered intraluminally and allowed to dwell for 20 min. Transgene expression was sought after 3 days by immunohistochemistry and at 7 days by quantitative reverse transcriptase PCR.The effect on intimal hyperplasia was sought using histological staining after 14 days. Evans blue staining was used to determine the effect on endothelial regeneration. eNOS and iNOS expression was detected in transduced arteries. Neointima/media ratios were significantly reduced in eNOS (0.0770.044) and iNOS (0.08770.086) transduced arteries compared with Adb-Gal (0.33270.14) transduced arteries (n ¼ 7). In addition, AdeNOS treatment (4.2173.12% deendothelialized area) enhanced endothelial regeneration compared to Adb-Gal treatment (10.0574.98), while treatment with AdiNOS (25.17711.92) inhibited endothelial regeneration in the injured rabbit carotid artery (n ¼ 7-8). These results highlight the potential of NOS gene therapy, in particular, eNOS gene therapy as a potential therapeutic strategy for the prevention of restenosis after vascular injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury

et al. 2006

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“…Recent studies have indicated that collagen accumulation and endothelial dysfunction are associated with constrictive remodeling. 34 Because endothelial vasodilator function is fairly preserved in our porcine model, 35 inflammatory vascular changes associated with collagen accumulation (especially at the adventitia) may play a primary role in the vascular remodeling.…”

Section: Rho-kinase As a Novel Therapeutic Target In Treatment Of Artmentioning

confidence: 97%

Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo

Morishige

Shimokawa

Eto

et al. 2001

ATVB

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Abstract-Small GTPase Rho and its target Rho-kinase/ROK/ROCK play an important role in various cellular functions, including smooth muscle contraction, actin cytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that adenovirus-mediated transfer of dominantnegative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1␤, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of ␤-galactosidase, into the interleukin-1␤-treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospastic activity in 3 weeks. Western blot analysis showed that the phosphorylation of adducin and the ezrin/radixin/moesin family, the target proteins of Rho-kinase, were upregulated at the coronary lesions and were significantly suppressed by the transfer of DNRhoK. Recent studies in vitro have suggested that the small GTP-binding protein Rho and its target protein Rho-kinase/ ROK/ROCK 2-4 play an important role in various cellular functions, including smooth muscle contraction, 5,6 actin cytoskeleton organization, 7,8 cell adhesion and motility, 9 cytokinesis, 10 and gene expression, 11 all of which may be involved in the pathogenesis of arteriosclerosis. We have recently demonstrated that Rho-kinase is functionally upregulated at the inflammatory coronary lesions and plays an important role in the pathogenesis of coronary hyperconstriction in our porcine model with interleukin (IL)-1␤. 12 The IL-1␤-treated coronary segment is characterized by luminal reduction caused by neointimal formation and constrictive remodeling. 13 Thus, our porcine model may be useful in the examination of the molecular mechanism of coronary arteriosclerosis in humans.We have recently found that hydroxyfasudil, an active metabolite of fasudil after oral absorption, is a potent and specific inhibitor of Rho-kinase and markedly inhibits coronary hyperconstriction and macrophage migration. 14,15 Thus, it is conceivable that Rho-kinase is involved not only in the pathogenesis of coronary artery spasm but also in that of coronary arteriosclerosis.To test this hypothesis, we examined in the present study whether selective inhibition of Rho-kinase by the local adenovirus-mediated transfer of dominant-negative Rhokinase (DNRhoK) can effectively induce a regression of coronary arteriosclerotic lesions in our porcine model in vivo. MethodsThis experiment was reviewed by the Committee of the Ethics on Animal Experiments at Kyushu University and was carried out under the control of the Guidelines for Animal Experiments at Kyushu University. Animal PreparationDomestic male pigs (2 to 3 months old, weighing 25 to 30 kg) were sedated with intramuscular ketamine hydrochloride...

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“…Collagen matrix 2 and cytoskeletal restructuring 1,6,7 are cornerstones of vascular remodeling. We investigated pecPDI effects in arterial collagen under polarized light.…”

Section: Disrupted Matrix/cytoskeletal Architecture Accounts For Pdiamentioning

confidence: 99%

“…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][2][3] or native atherosclerosis. 1,4 Moreover, cellular mechanisms governing conductance vessel remodeling are likely shared by small-vessel remodeling, for example, in hypertension.…”

mentioning

confidence: 99%

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

et al. 2016

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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...

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Endothelial Dysfunction and Collagen Accumulation

Abstract: These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.

Cited by 113 publications

References 40 publications

Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury

Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury

Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo

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

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