scholarly journals Partial endothelial-to-mesenchymal transition (EndMT) contributes to lumen re-organization after carotid artery ligation

2021 ◽  
Author(s):  
Yoshito Yamashiro ◽  
Karina Ramirez ◽  
Kazuaki Nagayama ◽  
Shuhei Tomita ◽  
Yoshiaki Kubota ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Vascular Remodeling ◽  
Early Stage ◽  
Cell Junctions ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Mesenchymal Transition ◽  
Carotid Artery Ligation ◽  
Endothelial To Mesenchymal Transition ◽  
Cell Cell

Endothelial-to-mesenchymal transition (EndMT) is a fundamental process in vascular remodeling. Carotid artery ligation is commonly used for induction of neointima formation and vessel stenosis; however, the precise regulatory mechanism of vascular remodeling is not entirely understood. In this study, we showed that resident endothelial cells (ECs) are the origin of neointima cells and ECs transiently expressed CD45 in the early stage of neointima formation accompanied by increased expression of EndMT markers. In vitro, CD45-positive EndMT was induced by stabilization of HIF-1α with cobalt chloride or VHL inhibitor in human primary ECs, which mimicked the hypoxic condition of ligated artery, and promoted the formation of integrin α11-SHARPIN complex. Notably, a CD45 phosphatase inhibitor disrupted this complex, thereby destabilizing cell-cell junctions. These results suggest that the CD45 activity is required for the retention of an EC phenotype and cell-cell junctions during EndMT (termed partial EndMT). We thus propose a novel mechanism of partial EndMT that contributes to lumen re-organization during vascular injury.

scholarly journals Hepatocyte gp130 Deficiency Reduces Vascular Remodeling After Carotid Artery Ligation

Hypertension ◽  
2009 ◽  
Vol 54 (5) ◽  
pp. 1035-1042 ◽  
Author(s):  
Gustavo Salguero ◽  
Harald Schuett ◽  
Joanna Jagielska ◽  
René Schley ◽  
Ezequiel Tallone ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Vascular Remodeling ◽  
Artery Ligation ◽  
Carotid Artery Ligation

scholarly journals Three-Dimensional Imaging Provides Detailed Atherosclerotic Plaque Morphology and Reveals Angiogenesis After Carotid Artery Ligation

2020 ◽  
Vol 126 (5) ◽  
pp. 619-632 ◽  
Author(s):  
Tobias Becher ◽  
Dario F. Riascos-Bernal ◽  
Daniel J. Kramer ◽  
Vanessa M. Almonte ◽  
Jingy Chi ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Mouse Models ◽  
Light Sheet ◽  
Volumetric Analysis ◽  
Neointima Formation ◽  
Plaque Volume ◽  
Artery Ligation ◽  
Light Sheet Microscopy ◽  
Carotid Artery Ligation ◽  
Brachiocephalic Arteries

Rationale: Remodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex processes evolves, there is a need to develop new imaging techniques to study underlying mechanisms. Objective: We used tissue clearing and light-sheet microscopy for 3-dimensional (3D) profiling of the vascular response to carotid artery ligation and induction of atherosclerosis in mouse models. Methods and Results: Adipo-Clear and immunolabeling in combination with light-sheet microscopy were applied to image carotid arteries and brachiocephalic arteries, allowing for 3D reconstruction of vessel architecture. Entire 3D neointima formations with different geometries were observed within the carotid artery and scored by volumetric analysis. Additionally, we identified a CD31-positive adventitial plexus after ligation of the carotid artery that evolved and matured over time. We also used this method to characterize plaque extent and composition in the brachiocephalic arteries of ApoE-deficient mice on high-fat diet. The plaques exhibited inter-animal differences in terms of plaque volume, geometry, and ratio of acellular core to plaque volume. A 3D reconstruction of the endothelium overlying the plaque was also generated. Conclusions: We present a novel approach to characterize vascular remodeling in adult mice using Adipo-Clear in combination with light-sheet microscopy. Our method reconstructs 3D neointima formation after arterial injury and allows for volumetric analysis of remodeling, in addition to revealing angiogenesis and maturation of a plexus surrounding the carotid artery. This method generates complete 3D reconstructions of atherosclerotic plaques and uncovers their volume, geometry, acellular component, surface, and spatial position within the brachiocephalic arteries. Our approach may be used in a number of mouse models of cardiovascular disease to assess vessel geometry and volume. Visual Overview: An online visual overview is available for this article.

scholarly journals Calreticulin Regulates Neointima Formation and Collagen Deposition following Carotid Artery Ligation

2015 ◽  
Vol 52 (5) ◽  
pp. 306-320 ◽  
Author(s):  
Kurt A. Zimmerman ◽  
Dongqi Xing ◽  
Manuel A. Pallero ◽  
Ailing Lu ◽  
Masahito Ikawa ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Neointima Formation ◽  
Collagen Deposition ◽  
Artery Ligation ◽  
Carotid Artery Ligation

Abstract 362: Ccn1 Induction and Its Role in the Neointima Formation-induced by Carotid Artery Ligation in Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Pei-Ling Hsu ◽  
Jheng-Sin Chen ◽  
Fan E Mo
Keyword(s):  
Carotid Artery ◽  
Common Carotid Artery ◽  
Matrix Protein ◽  
Extracellular Matrix Protein ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Disturbed Flow ◽  
Carotid Artery Ligation ◽  
The Right ◽  
Integrin Α6β1

Aim: Atherosclerosis, characterized by neointima formation, occurs preferentially at areas of disturbed flow. Extracellular matrix protein CCN1 is upregulated at the site of atherosclerotic lesions in humans and in animal models. Our aim was to examine the expression of CCN1-regulated by disturbed flow and its role in neointima formation. Methods and Results: Ccn1+/lacZ mice, in which a lacZ reporter gene was inserted to be driven by Ccn1-promoter, were subjected to complete ligation of the left common carotid artery. Progressive reduction in luminal diameters of the ligated artery were observed using B mode ultrasound compared with the right common carotid artery. Ccn1 expression, assessed by whole-mount X-gal staining, was detected in the intima and the media of carotid arteries 3 days after ligation, and the staining intensified between 1-4 weeks in the neointima after ligation. Specifically, Ccn1 expression was observed in endothelial cells, smooth muscle cells, and macrophages in the neointima. To dissect the role of CCN1 in the development of arterial lesions, knock-in mice carrying the integrin α6β1-binding-deficient mutant allele Ccn1-dm were tested in the carotid artery ligation model. Compared with wild-type mice, Ccn1dm/dm mice displayed significantly less neointima after ligation with improved endothelial function, less endothelial apoptosis, and lower oxidative stress, suggesting that the arterial expression of CCN1 induces endothelial dysfunction through its receptor integrin α6β1. Conclusions: CCN1 is a critical pathophysiological regulator mediating neointima formation induced by disturbed flow-generated after carotid artery ligation. CCN1 and its receptor integrin α6β1 represent potential therapeutic targets for atherosclerosis.

Abstract 307: Deficiency of Lim-only Protein Fhl2 Accelerates Neointima Formation After Carotid Artery Ligation

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Kondababu Kurakula ◽  
Vivian de Waard ◽  
Claudia M van Tiel ◽  
Carlie J de Vries
Keyword(s):  
Carotid Artery ◽  
Vascular Injury ◽  
Regulatory Function ◽  
Dependent Manner ◽  
Neointima Formation ◽  
Wild Type ◽  
Lesion Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
Enhanced Expression

Rationale The LIM-only protein FHL2, also known as DRAL or SLIM3, has a regulatory function in many physiological processes and is expressed in the vessel wall in smooth muscle cells (SMCs) and endothelial cells, but not in macrophages. FHL2 regulates SMC phenotype, but its function in vascular injury is unknown. Objective To assess the role of FHL2 in SMC-rich lesion formation after vascular injury and to elucidate the underlying mechanism. Methods & Results Cultured aortic SMCs from FHL2-KO mice showed increased migration and increased proliferation through enhanced phosphorylation of extracellular-regulated kinase-1/2 (ERK1/2) and induction of CyclinD1 expression. In agreement with this, overexpression of FHL2 in SMCs reduced CyclinD1 expression. In addition, FHL2-KO SMCs showed enhanced expression of pro-inflammatory cytokines in a NFkB dependent manner. Consistent with these findings, NFkB activity is higher in FHL2-KO SMCs. In response to carotid artery ligation FHL2-deficient (FHL2-KO) mice developed accelerated lesion formation compared with wild-type (WT)-mice. Furthermore, FHL2-KO mice displayed high number of macrophages in lesions and enhanced expression of RANTES and stromal derived factor-1α (SDF-1α) in ligated carotid arteries. SDF-1α expression was also increased in plasma of FHL2-KO mice. Finally, FHL2-KO mice showed enhanced Ki67 expression in lesions compared with wild-type (WT)-mice. Conclusion FHL2 deficiency in mice results in an exacerbated neointima formation by enhanced proliferation and migration of SMCs, possibly regulated via ERK1/2 and NFkB pathway.

scholarly journals Contribution of PDGFRα-positive cells in maintenance and injury responses in mouse large vessels

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kenichi Kimura ◽  
Karina Ramirez ◽  
Tram Anh Vu Nguyen ◽  
Yoshito Yamashiro ◽  
Aiko Sada ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Pressure Overload ◽  
Vascular Diseases ◽  
Cell Types ◽  
Lineage Tracing ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
Factor Receptor Alpha ◽  
Adventitial Cells

AbstractThe maladaptive remodeling of vessel walls with neointima formation is a common feature of proliferative vascular diseases. It has been proposed that neointima formation is caused by the dedifferentiation of mature smooth muscle cells (SMCs). Recent evidence suggests that adventitial cells also participate in neointima formation; however, their cellular dynamics are not fully understood. In this study, we utilized a lineage tracing model of platelet-derived growth factor receptor alpha (PDGFRa) cells and examined cellular behavior during homeostasis and injury response. PDGFRa marked adventitial cells that were largely positive for Sca1 and a portion of medial SMCs, and both cell types were maintained for 2 years. Upon carotid artery ligation, PDGFRa-positive (+) cells were slowly recruited to the neointima and exhibited an immature SMC phenotype. In contrast, in a more severe wire denudation injury, PDGFRa+ cells were recruited to the neointima within 14 days and fully differentiated into SMCs. Under pressure overload induced by transverse aortic constriction, PDGFRa+ cells developed marked adventitial fibrosis. Taken together, our observations suggest that PDGFRa+ cells serve as a reservoir of adventitial cells and a subset of medial SMCs and underscore their context-dependent response to vascular injuries.

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