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Fibroblast to myofibroblast transformation. Characteristics and inducers of transformation are indicated for adventitial fibroblasts, adventitial proto-myofibroblasts, and adventitial myofibroblasts. Figure created using Biorender.com accessed on 14 January 2022.
Source publication
Aortic aneurysm (AA) is a degenerative vascular disease that involves aortic dilatation, and, if untreated, it can lead to rupture. Despite its significant impact on the healthcare system, its multifactorial nature and elusive pathophysiology contribute to limited therapeutic interventions that prevent the progression of AA. Thus, further research...
Contexts in source publication
Context 1
... precursor and intermediate phenotype during the fibroblast to myofibroblast transformation has been documented and termed the proto-myofibroblast [78,89,91,93,100]. These proto-myofibroblasts have stress fibers but lack α-SMA, and they have increased proliferative and migratory activities compared to activated myofibroblasts (Figure 2) [89,91,93,101]. stress fibers, which causes the myofibroblasts to exhibit contractile activity [82,93,99]. ...
Context 2
... precursor and intermediate phenotype during the fibroblast to myofibroblast transformation has been documented and termed the proto-myofibroblast [78,89,91,93,100]. These proto-myofibroblasts have stress fibers but lack α-SMA, and they have increased proliferative and migratory activities compared to activated myofibroblasts (Figure 2) [89,91,93,101]. Myofibroblasts are the primary cell type implicated in pathological perivascular fibrosis, which is characterized by maladaptive ECM remodeling and the accumulation of collagen in the adventitial region [34,35,82,102]. ...
Citations
... Moreover, older and more recent studies have recognized the prominent role of adventitial resident cells and adventitial vessels as initiating factors of vessel wall inflammation [9,[21][22][23][24][25]. ...
Pathological studies have demonstrated that the adventitial layer is markedly thickened in Takayasu (TAK) as compared to large vessel giant cell arteritis (LV-GCA). An ultrasound (US) examination of the arterial vessels allows the determination of intima media thickness (IMT) and of adventitial layer thickness (extra media thickness (EMT)). No previous study has evaluated if there are differences in EMT thickness between TAK and LV-GCA. In this cross-sectional retrospective study of stored ultrasound (US) imaging, we have compared common carotid artery (CCA) EMT and IMT in a series of consecutive TAK and LV-GCA patients. US examination CCA IMT and EMT were significantly higher in TAK as compared to LV-GCA. With ROC curve analysis, we have found that an EMT > 0.76 mm has high sensitivity and specificity for TAK CCA examination. The percentage of CCA at EMT > 0.76 mm and the total arterial wall thickening were significantly higher in TAK group examinations. EMT thickness correlated with disease duration and IMT in the TAK group, as well as with the IMT and ESR values in the LV-GCA group. Upon multivariate logistic regression analysis, factors independently associated with TAK CCA were EMT > 0.76 mm and age. No significant variation in IMT and EMT could be demonstrated in subsequent US CCA examinations.
... To investigate further, we changed the location of MT1-MMP in aortic fibroblasts. Aortic fibroblasts are a key constituent of the aortic wall and maintain vessel structure and function [18]. We found that MT1-MMP must be internalized from the plasma membrane for the cell to secrete EMMPRIN in aortic fibroblasts. ...
Background: Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave the way they do in other cardiovascular pathologies. EMMPRIN is shed into the circulation through the secretion of extracellular vesicles. This has been demonstrated to be dependent upon the Membrane Type-1 MMP (MT1-MMP). We investigated this relationship in MFS TAA tissue and plasma to discern why unique profiles may exist. Methods: Protein targets were measured in aortic tissue and plasma from MFS patients with TAAs and were compared to healthy controls. The abundance and location of MT1-MMP was modified in aortic fibroblasts and secreted EMMPRIN was measured in conditioned culture media. Results: EMMPRIN levels were elevated in MFS TAA tissue but reduced in plasma, compared to the controls. Tissue EMMPRIN elevation did not induce MMP-3, MMP-8, or TIMP-1 expression, while MT1-MMP and TIMP-2 were elevated. MMP-2 and MMP-9 were reduced in TAA tissue but increased in plasma. In aortic fibroblasts, EMMPRIN secretion required the internalization of MT1-MMP. Conclusions: In MFS, impaired EMMPRIN secretion likely contributes to higher tissue levels, influenced by MT1-MMP cellular localization. Low EMMPRIN levels, in conjunction with other MMP analytes, distinguished MFS TAAs from controls, suggesting diagnostic potential.
... The adventitial layer has a role in remodelling the aortic wall in response to mechanical stress (68). In such conditions, fibroblasts undergo phenotype switching to myofibroblasts which deposit collagen and invoke an inflammatory response (69). Abnormal activation of this pathway contributes to abnormal ECM remodelling and can lead to reduced integrity. ...
Thoracic aortic disease (TAD) is often silent until a life-threatening complication occurs. However, genetic information can inform both identification and treatment at an early stage. Indeed, a diagnosis is important for personalised surveillance and intervention plans, as well as cascade screening of family members. Currently, only 20% of heritable TAD patients have a causative mutation identified and, consequently, further advances in genetic coverage are required to define the remaining molecular landscape. The rapid expansion of next generation sequencing technologies is providing a huge resource of genetic data, but a critical issue remains in functionally validating these findings. Induced pluripotent stem cells (iPSCs) are patient-derived, reprogrammed cell lines which allow mechanistic insights, complex modelling of genetic disease and a platform to study aortic genetic variants. This review will address the need for iPSCs as a frontline diagnostic tool to evaluate variants identified by genomic discovery studies and explore their evolving role in biological insight through to drug discovery.
... Dysregulation of ECM, however, may lead to severe vascular diseases, such as Marfan's syndrome [9]. The tunica adventitia is the most heterogenous layer in the vessel wall comprising fibroblasts, pericytes, progenitor cells, resident macrophages, and neurons [10,11]. The role of the adventitia in vascular diseases was historically overlooked since major efforts were focused on the tunica intima and media. ...
Vascular diseases, including atherosclerosis and abdominal aneurysms, are the primary cause of mortality and morbidity among the elderly worldwide. The life quality of patients is significantly compromised due to inadequate therapeutic approaches and limited drug targets. To expand our comprehension of vascular diseases, gene knockout (KO) mice, especially conditional knockout (cKO) mice, are widely used for investigating gene function and mechanisms of action. The Cre-loxP system is the most common method for generating cKO mice. Numerous Cre driver mice have been established to study the main cell types that compose blood vessels, including endothelial cells, smooth muscle cells, and fibroblasts. Here, we first discuss the characteristics of each layer of the arterial wall. Next, we provide an overview of the representative Cre driver mice utilized for each of the major cell types in the vessel wall and their most recent applications in vascular biology. We then go over Cre toxicity and discuss the practical methods for minimizing Cre interference in experimental outcomes. Finally, we look into the future of tissue-specific Cre drivers by introducing the revolutionary single-cell RNA sequencing and dual recombinase system.
... Previous studies have focused on the important roles of inflammatory cells and VSMCs in AA occurrence and development. Fibroblasts, which are the main cell component of the adventitia, are important in maintaining the stability of the arterial structure and function [71]. However, the pathological mechanisms of fibroblasts in AA/AD have rarely been reported. ...
... In addition, fibroblasts are the main cell components of the adventitia. In the early stages of pathological changes, the activation of fibroblasts may cause their differentiation into myofibroblasts, thereby enhancing contraction, migration, and proliferation, promoting the production of cytokines and chemokines, and leading to ECM remodeling [71]. In rheumatoid arthritis, cancer, and inflammatory bowel disease, fibroblasts have been shown to drive angiogenesis in tissues [142,143]. ...
Aortic aneurysm and aortic dissection (AA/AD) are critical aortic diseases with a hidden onset and sudden rupture, usually resulting in an inevitable death. Several pro- and anti-angiogenic factors that induce new capillary formation in the existing blood vessels regulate angiogenesis. In addition, aortic disease mainly manifests as the proliferation and migration of endothelial cells of the adventitia vasa vasorum. An increasing number of studies have shown that angiogenesis is a characteristic change that may promote AA/AD occurrence, progression, and rupture. Furthermore, neocapillaries are leaky and highly susceptible to injury by cytotoxic agents, which promote extracellular matrix remodeling, facilitate inflammatory cell infiltration, and release coagulation factors and proteases within the wall. Mechanistically, inflammation, hypoxia, and angiogenic factor signaling play important roles in angiogenesis in AA/AD under the complex interaction of multiple cell types, such as smooth muscle cells, fibroblasts, macrophages, mast cells, and neutrophils. Therefore, based on current evidence, this review aims to discuss the manifestation, pathological role, and underlying mechanisms of angiogenesis involved in AA/AD, providing insights into the prevention and treatment of AA/AD.
... Sympathetic nerve endings, which are primarily located in the arterial vascular adventitia, release NE. The sympathetic nerves primarily innervate the adventitia of the artery but rarely innervate the media of the artery (44). However, as a key regulator in neurohumoral regulation, the roles of NE in vascular adventitia remain unclear. ...
Vascular remodeling caused by vascular injury such as hypertension and atherosclerosis is a complex process involving a variety of cells and factors, and the mechanism is unclear. A vascular injury model was simulated by adding norepinephrine (NE) to culture medium of vascular adventitial fibroblasts (AFs). NE induced activation and proliferation of AFs. To investigate the association between the AFs activation and bone marrow mesenchymal stem cells (BMSCs) differentiation in vascular remodeling. BMSCs were cultured with supernatant of the AFs culture medium. BMSC differentiation and migration were observed by immunostaining and Transwell assay, respectively, while cell proliferation was measured using the Cell Counting Kit-8. Expression levels of smooth muscle actin (α-SMA), TGF-β1 and SMAD3 were measured using western blot assay. The results indicated that compared with those in the control group, in which BMSCs were cultured in normal medium, expression levels of α-SMA, TGF-β1 and SMAD3 in BMSCs cultured in medium supplemented with supernatant of AFs, increased significantly (all P<0.05). Activated AFs induced the differentiation of BMSCs into vascular smooth muscle-like cells and promoted proliferation and migration. AFs activated by NE may induce BMSCs to participate in vascular remodeling. These findings may help design and develop new approaches and therapeutic strategies for vascular injury to prevent pathological remodeling.
... Mechanical stress and inflammatory signals are vital cues for fibroblast activation, and factors involved in mediating transduction between mechanical/inflammatory signals and fibroblasts are crucial in fibrotic diseases, especially atherosclerosis [7,8]. The extracellular matrix (ECM), as one of the most important constituents of the cell microenvironment, can be produced by adventitial fibroblasts and in turn affects the activation of adventitial fibroblasts [9]. Periostin (POSTN), a matricellular protein, has been found to promote the profibrotic phenotype of human skin fibroblasts [10], facilitate wound healing [11,12], and participate in various skin diseases [13e15]. ...
... Most studies on atherosclerosis are focused on the intima and media, while the understanding of the roles of adventitia in the pathogenesis of atherosclerosis is much less. However, recent works have found that the adventitia is not merely a supporting structure of vessels but also participates in the adaptation and modulation of vascular pathologies, including atherosclerosis [9,36]. POSTN, a secreted extracellular matrix protein, has been demonstrated to function in the intimate and media during atherosclerosis, and loss of POSTN delays atherosclerosis progression by modulating atherosclerotic plaque architecture and inflammatory cell infiltration [37]. ...
Background and aims
Adventitial remodeling is an important pathological process of arteriosclerosis, but cues implicated in adventitia remodeling are far from fully understood. Periostin (POSTN), a matricellular protein, has been demonstrated to have multiple roles in cardiovascular diseases. The aim of the study was to explore the function of POSTN in adventitia remodeling during atherosclerosis.
Methods
An atherosclerosis model was constructed based on ApoE-/- mice fed a high-fat and high-cholesterol diet. The expression of POSTN in the adventitia of mouse arteriosclerotic vascular specimens was detected by immunohistochemical staining. The roles of POSTN in regulating adventitial fibroblast activation were assessed by cell contractility and activation marker α-smooth muscle actin (α-SMA) expression evaluation in adventitial fibroblasts overexpressing POSTN. In addition, we performed qPCR and Western blotting to examine the expression of the proinflammatory chemokines transforming growth factor-β1 (TGF-β1) and monocyte chemotactic protein 1 (MCP1), as well as some ECM-related proteins, in POSTN-overexpressing adventitial fibroblasts. Finally, the integrin-related signaling pathway was detected upon POSTN overexpression in adventitial fibroblasts.
Results
POSTN was highly expressed in the adventitia of atherosclerotic aortae in the mouse arteriosclerosis model and promoted the activation and contraction of adventitial fibroblasts. Meanwhile, POSTN also induced adventitial fibroblasts to express TGF-β1, MCP1, and ECM-related proteins and activated the phosphorylation of focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src).
Conclusions
Our results revealed that POSTN is elevated in adventitia during atherosclerosis and contributes to the adventitial remodeling of arteriosclerosis by activating adventitial fibroblasts.
... Probably, a synergistic action of all these elements reflects the different AAA phenotypes associated with BAV, as stressed in our works, than those detected in TAV individuals [4,10,12]. Differently, TAV subjects show a more advanced age of AAA onset, about versus the 70-75 years, and a pathogenesis more related to vascular aging and the resultant remodeling and degeneration process associated with a preeminent fibrosis, that significantly reduces the probability of AAA progression in dissection and rupture [2,[13][14][15][16][17]. Precisely, a typical vascular remodeling and degeneration, accompanied by wound healing associated with a significant increase of circulating EPC levels [9,11], tissue expression of TGF-β and Smad-3 [18][19][20][21] consequent inflammation, endothelial-to-mesenchymal transition (EndMT) [22][23][24] and fibrosis [25], embody aorta dilation, or better, AAA disease, in TAV patients. ...
The pathobiology of ascending aorta aneurysms (AAA) onset and progression is not well understood and only partially characterized. AAA are also complicated in case of bicuspid aorta valve (BAV) anatomy. There is emerging evidence about the crucial role of endothelium-related pathways, which show in AAA an altered expression and function. Here, we examined the involvement of ERG-related pathways in the differential progression of disease in aortic tissues from patients having a BAV or tricuspid aorta valve (TAV) with or without AAA. Our findings identified ERG as a novel endothelial-specific regulator of TGF-β-SMAD, Notch, and NO pathways, by modulating a differential fibrotic or calcified AAA progression in BAV and TAV aortas. We provided evidence that calcification is correlated to different ERG expression (as gene and protein), which appears to be under control of Notch signaling. The latter, when increased, associated with an early calcification in aortas with BAV valve and aneurysmatic, was demonstrated to favor the progression versus severe complications, i.e., dissection or rupture. In TAV aneurysmatic aortas, ERG appeared to modulate fibrosis. Therefore, we proposed that ERG may represent a sensitive tissue biomarker to monitor AAA progression and a target to develop therapeutic strategies and influence surgical procedures.
Aims:
Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases but their role in AAA is poorly understood.
Methods and results:
The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the ECM. They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodeling but also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity results in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity was also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodeling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall.
Conclusion:
In conclusion, our data strongly supports the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients.
The availability of grafts to replace small‐diameter arteries remains an unmet clinical need. Here, the validated methodology is reported for a novel hybrid tissue‐engineered vascular graft that aims to match the natural structure of small‐size arteries. The blood vessel mimic (BVM) comprises an internal conduit of co‐electrospun gelatin and polycaprolactone (PCL) nanofibers (corresponding to the tunica intima of an artery), reinforced by an additional layer of PCL aligned fibers (the internal elastic membrane). Endothelial cells are deposited onto the luminal surface using a rotative bioreactor. A bioprinting system extrudes two concentric cell‐laden hydrogel layers containing respectively vascular smooth muscle cells and pericytes to create the tunica media and adventitia. The semi‐automated cellularization process reduces the production and maturation time to 6 days. After the evaluation of mechanical properties, cellular viability, hemocompatibility, and suturability, the BVM is successfully implanted in the left pulmonary artery of swine. Here, the BVM showed good hemostatic properties, capability to withstand blood pressure, and patency at 5 weeks post‐implantation. These promising data open a new avenue to developing an artery‐like product for reconstructing small‐diameter blood vessels.
