Upregulation of connexin43 gap junctions between neointimal smooth muscle cells

Plenz, Gabriele; Ko, Yousang; Yeh, Hung‐I; Eschert, Heike; Sindermann, Jürgen R.; Dorszewski, Anja; Hofnagel, Oliver; Robenek, Horst; Breithardt, G.; Severs, Nicholas J.

doi:10.1078/0171-9335-00417

Cited by 18 publications

(16 citation statements)

References 19 publications

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“…16 Enhanced Cx43 expression in vascular SMCs and neointimal macrophages was reported later in restenotic lesions of injured rabbits. 17,18 Indeed, in vitro studies confirmed the presence of Cx43 in stimulated primary macrophages or in macrophage cell lines. 19,20 However, the formation of functional gap junction channels in leukocytes is not clearly established.…”

Section: Clinical Perspective P 2843mentioning

confidence: 75%

Reduced Connexin43 Expression Limits Neointima Formation After Balloon Distension Injury in Hypercholesterolemic Mice

et al. 2006

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Background— Reducing the expression of the gap junction protein connexin43 (Cx43) inhibits the progression of atherosclerosis, a chronic inflammatory disease. Furthermore, acute vascular injury induced by percutaneous coronary interventions is associated with increased Cx43 expression in neointimal smooth muscle cells (SMCs). However, the relevance of Cx43 after acute vascular injury remains unclear. Methods and Results— To investigate whether reducing Cx43 expression would affect neointima formation in vivo, we subjected hypercholesterolemic Cx43 +/− LDL receptor–deficient (LDLR −/− ) mice and Cx43 +/+ LDLR −/− control littermates to carotid balloon distension injury, which induced marked endothelial denudation and activation of medial SMCs. We observed decreased macrophage infiltration in Cx43 +/− LDLR −/− mice 7 days after injury. Similarly, peritoneal macrophages isolated from Cx43 +/− LDLR −/− mice showed reduced migration in vitro compared with Cx43 +/+ LDLR −/− macrophages. Interestingly, Cx43 +/− LDLR −/− macrophages also displayed decreased chemotactic activity for SMCs. In addition, we observed less SMC infiltration and proliferation in Cx43 +/− LDLR −/− mice 7 and 14 days after balloon angioplasty. Likewise, Cx43 +/− LDLR −/− SMCs showed decreased proliferation and migration in vitro compared with Cx43 +/+ LDLR −/− cells. All these events resulted in a reduction of neointimal thickening after vascular injury in Cx43 +/− LDLR −/− mice. Conclusions— The present study shows for the first time that reducing Cx43 limits neointima formation after acute vascular injury by decreasing the inflammatory response and reducing SMC migration and proliferation. Thus, decreasing Cx43 expression may offer a novel therapeutic strategy for reducing restenosis after percutaneous coronary intervention.

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Section: Clinical Perspective P 2843mentioning

confidence: 75%

Reduced Connexin43 Expression Limits Neointima Formation After Balloon Distension Injury in Hypercholesterolemic Mice

et al. 2006

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“…Enhanced intimal Cx43 expression was also reported in restenotic lesions of injured vessels in other species. 24,25,42,43 These studies suggested that Cx43 expression levels in vascular SMCs are intimately linked to their phenotype. In agreement with this notion, it has been reported that cytokine-induced modulation of cultured SMCs from a differentiated to a dedifferentiated state coincided with more numerous and larger gap junctions as well as increased expression of Cx43.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, increased intimal expression of Cx43 has been observed during the growing phase of human and mouse atherosclerotic lesions, 20,21 and reducing Cx43 restricts atherosclerotic plaque development in mice. 22 Similarly, balloon distension, as well as wire injury in animal models, results in increased Cx43 expression in the IT, [23][24][25][26] and reducing Cx43 expression changes the course of the restenotic process in mice. 25,27 These in vivo studies suggest that Cx43 could be associated to SMC phenotype, a concept also proposed after cytokine-or growth factor-induced dedifferentiation of SMCs.…”

mentioning

confidence: 99%

Targeting Connexin 43 Prevents Platelet-Derived Growth Factor-BB–Induced Phenotypic Change in Porcine Coronary Artery Smooth Muscle Cells

Chadjichristos

Morel

Derouette

et al. 2008

Circulation Research

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Abstract-We previously reported that reducing the expression of the gap junction protein connexin (Cx)43 in mice restricts intimal thickening formation after acute vascular injury by limiting the inflammatory response and the proliferation and migration of smooth muscle cells (SMCs) toward the damaged site. SMC populations isolated from porcine coronary artery exhibit distinct phenotypes: spindle-shaped (S) and rhomboid (R). S-SMCs are predominant in the normal media, whereas R-SMCs are recovered in higher proportion from stent-induced intimal thickening, suggesting that they participate in the restenotic process. Here, we further investigate the relationship between connexin expression and SMC phenotypes using porcine coronary artery SMCs. Cx40 was highly expressed in normal media of porcine coronary artery in vivo, whereas Cx43 was barely detectable. In contrast, Cx40 was downregulated and Cx43 was markedly upregulated in stent-induced intimal thickening. In vitro, S-SMCs expressed Cx40 and Cx43. In R-SMCs, Cx43 expression was increased and Cx40 was absent. We confirmed that S-SMCs treated with platelet-derived growth factor-BB acquire an R phenotype. This was accompanied by an upregulation of Cx43 and a loss of Cx40. Importantly, platelet-derived growth factor-BB-induced S-to-R phenotypic change was prevented by a reduction of Cx43 expression with antisense, ie, S-SMCs retained their typical elongated appearance and the expression of ␣-smooth muscle actin, a well-known SMC differentiation marker, whereas the expression of S100A4, a typical marker of R-SMCs, was prevented. In conclusion, limiting Cx43 expression in S-SMCs prevents platelet-derived growth factor-BB-induced S-to-R modulation. This suggests that Cx43 may be an additional target for local delivery strategies aimed at reducing restenosis. (Circ Res. 2008;102:653-660.)

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“…Moreover, a critical role for Cx43 has been reported in human saphenous vein during the development of intimal hyperplasia (Deglise et al 2005) and restenosis (Plenz et al 2004) and Cx43 decreases smooth muscle cell proliferation and limits neointima formation after vascular injury (Chadjichristos et al 2006). Conversely, regeneration of the endothelium following carotid artery injury in rats, a process essential for wound healing, is associated with increasing expression of Cx37, Cx40, and Cx43 (Yeh et al 2000).…”

Section: Sex Differences In Vessel Repairmentioning

confidence: 99%

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

Villar¹,

Hobbs²,

Ahluwalia

2008

Journal of Endocrinology

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The vascular endothelium plays a crucial role in the regulation of vascular homeostasis by controlling vascular tone, coagulation, and inflammatory responses. These actions are exerted by endothelial factors including nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). The greater incidence of cardiovascular disease (CVD) in men and postmenopausal women compared with premenopausal women implies a vasoprotective phenotype of females, which may be influenced by sex hormones. These hormones, particularly estrogen, have modulatory effects on the endothelium and circulating cells that have been implicated in vascular inflammation and in the development of CVD. EDHF seems to be the predominant endothelial factor in the resistance vasculature of females and this mediator could afford the beneficial cardiovascular risk profile observed in premenopausal woman. In this review, we discuss sex differences in EDHF biology and how sex hormones can modulate EDHF responses. We also review the implication of sex hormone-dependent regulation of EDHF in inflammatory processes, platelet function, and repair after vascular damage, each of which have a critical role in several aspects of the pathogenesis of CVD.

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Upregulation of connexin43 gap junctions between neointimal smooth muscle cells

Cited by 18 publications

References 19 publications

Reduced Connexin43 Expression Limits Neointima Formation After Balloon Distension Injury in Hypercholesterolemic Mice

Reduced Connexin43 Expression Limits Neointima Formation After Balloon Distension Injury in Hypercholesterolemic Mice

Targeting Connexin 43 Prevents Platelet-Derived Growth Factor-BB–Induced Phenotypic Change in Porcine Coronary Artery Smooth Muscle Cells

Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor

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