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Autoimmunity Reviews May 2024Large-vessel vasculitides (LVV) comprise a group of chronic inflammatory diseases of the aorta and its major branches. The most common forms of LVV are giant cell... (Review)
Review
Large-vessel vasculitides (LVV) comprise a group of chronic inflammatory diseases of the aorta and its major branches. The most common forms of LVV are giant cell arteritis (GCA) and Takayasu arteritis (TAK). Both GCA and TAK are characterized by granulomatous inflammation of the vessel wall accompanied by a maladaptive immune and vascular response that promotes vascular damage and remodeling. The inflammatory process in LVV starts in the adventitia where fibroblasts constitute the dominant cell population. Fibroblasts are traditionally recognized for synthesizing and renewing the extracellular matrix thereby being major players in maintenance of normal tissue architecture and in tissue repair. More recently, fibroblasts have emerged as a highly plastic cell population exerting various functions, including the regulation of local immune processes and organization of immune cells at the site of inflammation through production of cytokines, chemokines and growth factors as well as cell-cell interaction. In this review, we summarize and discuss the current knowledge on fibroblasts in LVV. Furthermore, we identify key questions that need to be addressed to fully understand the role of fibroblasts in the pathogenesis of LVV.
PubMed: 38782083
DOI: 10.1016/j.autrev.2024.103574 -
Research Square Aug 2023Alzheimer disease (AD) is a neurodegenerative disease and the main cause for dementia. The irreversible neurodegeneration leads to a gradual loss of brain function...
Alzheimer disease (AD) is a neurodegenerative disease and the main cause for dementia. The irreversible neurodegeneration leads to a gradual loss of brain function characterized predominantly by memory loss. Cerebrovascular changes are common neuropathologic findings in aged subjects with dementia. Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain, as cerebrovascular remodeling may render the brain more susceptible to pulse pressure and may be associated with poorer cognitive performance and greater risk of cerebrovascular events. The objective of this study is to provide understanding of cerebrovascular remodeling with AD progression. A total of 28 brain donor participants with human anterior cerebral artery (ACA) from controls and pathologically diagnosed AD groups (early - Braak stages I-II; intermediate - Braak stages III-IV; and advanced - Braak stages V-VI) were included in this study. Mechanical testing, histology, advanced optical imaging, and mass spectrometry were performed to study the progressive structural and functional changes of ACAs with AD progression. Biaxial extension-inflation tests showed that ACAs became progressively less compliant, and the longitudinal stress in the intermediate& advanced AD groups was significantly higher than that from the control group. With pathological AD development, the inner and outer diameter of ACA remained almost unchanged; however, histology study revealed progressive smooth muscle cell atrophy and loss of elastic fibers which led to compromised structural integrity of the arterial wall. Multiphoton imaging demonstrated elastin degradation at the media-adventitia interface, which led to the formation of an empty band of 21.0 ± 15.4 μm and 32.8 ± 9.24 μm in width for the intermediate& advanced AD groups, respectively. Furthermore, quantitative birefringence microscopy showed disorganized adventitial collagen with AD development. Mass spectrometry analysis provided further evidence of altered collagen content and other extracellular matrix (ECM) molecule and smooth muscle cell changes that were consistent with the mechanical and structural alterations. Collectively, our study provides understanding of the mechanical and structural cerebrovascular deterioration in cerebral arteries with AD, which may be related to neurodegenration and pathology in the brain.
PubMed: 37693508
DOI: 10.21203/rs.3.rs-3283587/v1 -
Biomolecules & Biomedicine Jul 2023The risk factors that are the most significant for the development of most cardiovascular diseases are arterial hypertension (AH), type 2 diabetes (DM), and...
The risk factors that are the most significant for the development of most cardiovascular diseases are arterial hypertension (AH), type 2 diabetes (DM), and inflammation. However, for the development of aortic aneurysms, DM is not one of them. Our study aimed to evaluate the difference between inflammatory infiltration in three individual layers of the ascending aortic aneurysm within diabetic and hypertensive patients. Forty-five patients aged 36 to 80 were divided into a group with diabetic patients without AH (group DM, N=8) and hypertensive patients without DM (group AH, N=37). For the histological analysis, aortic aneurysms were stained with hematoxylin eosin and Movat. We used immunochemical methods to detect pro- (M1), anti-inflammatory (M2) macrophages, T-helper, T-killer cells, B cells, and plasma cells. Statistical analysis was done by independent-samples Kruskal-Wallis test adjusted by Bonferroni correction for multiple tests (P<0.05). We found no difference in the volume density of collagen, elastin, vascular smooth muscle cells (VSMC), and ground substance between groups. In the DM group, there were significantly fewer M2, T-helpers, and T-killers in the media than in the intima and the adventitia (P<0.05). There were no significant differences in the number of M1, B, and plasma cells between all three vascular layers (P<0.05). In the AH group, there were significantly fewer B and plasma cells, T-helper, T-killer cells, M1, and M2 in the media than in the intima and adventitia (P<0.05). Our results conclude that the tunica media in the aneurismal wall of the AH group retained immune privilege. In contrast, in the DM group, all three layers were immune-privileged.
Topics: Humans; Adventitia; Diabetes Mellitus, Type 2; Aneurysm, Ascending Aorta; Aortic Aneurysm; Hypertension; Tunica Intima
PubMed: 36724019
DOI: 10.17305/bb.2022.8565 -
ERJ Open Research Nov 2023Epithelial-mesenchymal transition (EMT) might be central to lung cancer development in smokers and COPD. We illustrate EMT changes in a broader demographic of patient...
BACKGROUND
Epithelial-mesenchymal transition (EMT) might be central to lung cancer development in smokers and COPD. We illustrate EMT changes in a broader demographic of patient groups who were diagnosed with nonsmall cell lung cancer (adenocarcinoma and squamous cell carcinoma). These included COPD current and ex-smokers, patients with small airway disease and normal lung function smokers compared to normal controls.
METHODS
We had access to surgically resected small airway tissue from 46 subjects and assessed for airway wall thickness and immunohistochemically for the EMT biomarkers E-cadherin, N-cadherin, S100A4, vimentin and epidermal growth factor receptor (EGFR). All tissue analysis was done with a computer and microscope-assisted Image-Pro Plus 7.0 software.
RESULTS
Airway wall thickness significantly increased across all pathological groups (p<0.05) compared to normal controls. Small airway epithelial E-cadherin expression markedly decreased (p<0.01), and increases in N-cadherin, vimentin, S100A4 and EGFR expression were observed in all pathological groups compared to normal controls (p<0.01). Vimentin-positive cells in the reticular basement membrane, lamina propria and adventitia showed a similar trend to epithelium across all pathological groups (p<0.05); however, such changes were only observed in reticular basement membrane for S100A4 (p<0.05). Vimentin was higher in adenocarcinoma squamous cell carcinoma; in contrast, S100A4 was higher in the squamous cell carcinoma group. EGFR and N-cadherin expression in both phenotypes was markedly higher than E-cadherin, vimentin and S100A4 (p<0.0001).
CONCLUSION
EMT is an active process in the small airway of smokers and COPD diagnosed with nonsmall cell lung cancer, contributing to small airway remodelling and cancer development as seen in these patients.
PubMed: 38152085
DOI: 10.1183/23120541.00581-2023 -
Journal of Cell Communication and... Sep 2023Abdominal aortic aneurysms (AAA) have the highest incidence and rupture rate of all aortic aneurysms. The N6 methyladenosine (m6A) modification is closely associated...
METTL3-METTL14 complex induces necroptosis and inflammation of vascular smooth muscle cells via promoting N6 methyladenosine mRNA methylation of receptor-interacting protein 3 in abdominal aortic aneurysms.
Abdominal aortic aneurysms (AAA) have the highest incidence and rupture rate of all aortic aneurysms. The N6 methyladenosine (m6A) modification is closely associated with angiotensin (Ang II)-induced aortic diseases. This study aimed to identify whether the m6A writer METTL3/METTL4 regulates rip3 mRNA expression in AAA. To induce the mouse AAA model, apolipoprotein E-deficient (ApoE-/-) mice were subcutaneously infused with Ang II, and C57BL/6 mice were infused with type I elastase. Vascular smooth muscle cells (VSMCs) were induced with Ang II. Necroptosis was detected using an Annexin V-FITC/PI apoptosis detection kit, and ELISA assays measured inflammatory cytokines. The RNA immunoprecipitation-qPCR determined the methylated rip3 mRNA level. The increased expressions of inflammatory factors, aortic adventitia injury, degradation of elastin, and CD68-positive cells suggested the successful establishment of mouse AAA models. In AAA aorta wall tissues, the m6A modification level and the expression of METTL3/METTL14 were elevated. In Ang II-induced VSMCs, necroptosis and inflammatory cytokines in the supernatants were increased. RNA immunoprecipitation and co-immunoprecipitation assays confirmed the binding between the METTL3-METTL14 complex and rip3 mRNA, the interaction between YTHDF3 and rip3 mRNA, and between the METTL3-METTL14 complex and SMAD2/3. Interference with METTL3/METTL14 attenuated VSMC necroptosis, inflammatory response, and the AAA pathological process in vivo. The METTL3-METTL14 complex, which was increased by the activation of the SMAD2/3, elevated the m6A modification of rip3 mRNA by promoting the binding between YTHDF3 and rip3 mRNA, thus contributing to the progression of AAA. The activation of SMAD2/3 in VSMCs of abdominal aortic wall tissues is stimulated by Ang II. Subsequently, it promotes METTL3 METTL14 complex mediated m6A modification of rip3 mRNA. Meanwhile, the level of rip3 mRNA becomes more stable under the m6A reader of YTHDF3, which increases the protein level of RIP3 and further induces VSMC necroptosis. In addition, cell debris induces inflammatory factors in neighboring VSMCs and recruit monocytes/macrophages to the lesion.
PubMed: 36947363
DOI: 10.1007/s12079-023-00737-y -
Multimedia Manual of Cardiothoracic... Nov 2023The Ross-Personalized External Aortic Root Support procedure is a surgical aortic valve replacement technique in which the autologous pulmonary valve is transposed in...
The Ross-Personalized External Aortic Root Support procedure is a surgical aortic valve replacement technique in which the autologous pulmonary valve is transposed in the aortic position to replace the malfunctioning aortic valve and a homograft is implanted in the pulmonary position. To prevent autograft dilatation, a Personalized External Aortic Root Support prosthesis is included in the proximal autograft anastomosis and wrapped around the ascending aorta. The aorta is transected transversely, the aortic valve is resected, and the coronary arteries are mobilized and cut out of the sinuses, leaving a rim. The pulmonary autograft is harvested by transecting the pulmonary artery and part of the right ventricular outflow tract. The autograft is approximated to the aortic root and inverted inside the ventricle. The proximal anastomosis is performed including the prosthesis between the aortic root and the autograft. The coronary buttons are threaded through appropriately positioned and sized holes in the prosthesis and reimplanted into the autograft. The ascending aorta is appropriately adapted and anastomosed with the distal autograft. When the patient is off cardiopulmonary bypass, the prosthesis can be closed longitudinally and is anchored to the distal aortic adventitia.
Topics: Humans; Autografts; Aorta, Thoracic; Transplantation, Autologous; Aortic Valve; Aorta; Aortic Valve Stenosis; Aortic Valve Insufficiency; Pulmonary Valve; Heart Valve Prosthesis Implantation; Reoperation
PubMed: 37942704
DOI: 10.1510/mmcts.2023.077 -
JMA Journal Jul 2023Takayasu arteritis (TAK) is a type of large-vessel vasculitis that predominantly affects young females. The precise pathomechanism of TAK is still under investigation.... (Review)
Review
Takayasu arteritis (TAK) is a type of large-vessel vasculitis that predominantly affects young females. The precise pathomechanism of TAK is still under investigation. In TAK, the vasa vasorum is considered to be the initial inflammatory site. Disruption of the vasa vasorum induces the entry of inflammatory cells into the vascular wall of large vessels between the media and adventitia, and infiltrated cells damage the vascular components, eventually leading to stenosis or dilatation of the affected arteries. In addition, T cells are considered key players in TAK, and myeloid cells function as effector cells. Although the roles of B cells in TAK are poorly understood, recent evidence supports their contribution to the pathogenicity of TAK. Particularly, two autoantibodies have been identified in TAK through investigation of anti-endothelial cell antibodies, and they could be involved in the maintenance of vascular inflammation. Furthermore, one of the autoantibodies, anti-endothelial protein C receptor, was shown to be present in ulcerative colitis (UC), which is genetically and clinically associated with TAK. Similar autoantibodies in inflammatory diseases with different target organs indicate a common underlying pathophysiology of these diseases, which could be characterized by the aberrant activation of B cells. This review discusses recent understanding of the pathomechanisms of TAK and UC, with a focus on the involvement of B cells and autoantibodies. The close association of UC with TAK further suggests a common etiology, and the importance of the intestinal microbiota, including dysbiosis, is also becoming known in TAK. Investigation of such common factors among TAK and UC would improve understanding of the interplay between gut and vascular inflammation, which is a new concept for developing vascular inflammation through the gut-vessel connection.
PubMed: 37560375
DOI: 10.31662/jmaj.2023-0038 -
EJVES Vascular Forum 2023Calcification of a vascular endograft and adjacent tissues (adventitia, media, and neointima) can result in graft failure. This report shows a rare case of intraluminal...
INTRODUCTION
Calcification of a vascular endograft and adjacent tissues (adventitia, media, and neointima) can result in graft failure. This report shows a rare case of intraluminal calcifications in the distal end of a thoracic endovascular aortic repair (TEVAR) endograft implanted 11 years previously for grade IV blunt traumatic aortic injury (BTAI) in a young patient.
REPORT
A 24 year old man required TEVAR for a BTAI caused by a motorcycle accident. The procedure consisted of TEVAR and an emergency left carotid subclavian venous bypass. Eleven years after the procedure, he had severe hypertension. Intra-TEVAR calcifications appeared, gradually increasing on computed tomography angiography (CTA). Calcifications in the distal luminal end of the TEVAR were responsible for a 60% stenosis on CTA. An open approach was indicated after multidisciplinary discussion, based on the gradient value. The patient underwent explantation, with total replacement of the aortic arch and descending thoracic aorta with re-implantation of the supra-aortic vessels, under extracorporeal circulation. Macroscopic analysis showed no device degeneration but revealed a solid mass at the distal end of the TEVAR. Both microcomputed tomography and histopathology confirmed the calcific nature of the lesions.
CONCLUSION
This case highlights a rare long term graft failure due to calcified neo-atherosclerosis in a TEVAR.
PubMed: 37876922
DOI: 10.1016/j.ejvsvf.2023.09.006 -
Frontiers in Physiology 2023Mechanical stress and strain conditions are closely related to atherosclerotic plaque progression and rupture and have been under intensive investigations in recent...
Mechanical stress and strain conditions are closely related to atherosclerotic plaque progression and rupture and have been under intensive investigations in recent years. It is well known that arteries have a three-layer structure: intima, media and adventitia. However, image-based multilayer plaque models are not available in the current literature due to lack of multilayer image segmentation data. A multilayer segmentation and repairing technique was introduced to segment coronary plaque optical coherence tomography (OCT) image to obtain its three-layer vessel structure. A total of 200 OCT slices from 20 patients (13 male; 7 female) were used to construct multilayer and single-layer 3D thin-slice models to calculate plaque stress and strain and compare model differences. Our results indicated that the average maximum plaque stress values of 20 patients from multilayer and single-layer models were 385.13 ± 110.09 kPa and 270.91 ± 95.86 kPa, respectively. The relative difference was 42.2%, with single-layer stress serving as the base value. The average mean plaque stress values from multilayer and single-layer models were 129.59 ± 32.77 kPa and 93.27 ± 18.20 kPa, respectively, with a relative difference of 38.9%. The maximum and mean plaque strain values obtained from the multilayer models were 11.6% and 19.0% higher than those from the single-layer models. Similarly, the maximum and mean cap strains showed increases of 9.6% and 12.9% over those from the single-layer models. These findings suggest that use of multilayer models could improve plaque stress and strain calculation accuracy and may have large impact on plaque progression and vulnerability investigation and potential clinical applications. Further large-scale studies are needed to validate our findings.
PubMed: 37608838
DOI: 10.3389/fphys.2023.1251401 -
Arteriosclerosis, Thrombosis, and... Mar 2024The metabolic alterations occurring within the arterial architecture during atherosclerosis development remain poorly understood, let alone those particular to each... (Observational Study)
Observational Study
BACKGROUND
The metabolic alterations occurring within the arterial architecture during atherosclerosis development remain poorly understood, let alone those particular to each arterial tunica. We aimed first to identify, in a spatially resolved manner, the specific metabolic changes in plaque, media, adventitia, and cardiac tissue between control and atherosclerotic murine aortas. Second, we assessed their translatability to human tissue and plasma for cardiovascular risk estimation.
METHODS
In this observational study, mass spectrometry imaging (MSI) was applied to identify region-specific metabolic differences between atherosclerotic (n=11) and control (n=11) aortas from low-density lipoprotein receptor-deficient mice, via histology-guided virtual microdissection. Early and advanced plaques were compared within the same atherosclerotic animals. Progression metabolites were further analyzed by MSI in 9 human atherosclerotic carotids and by targeted mass spectrometry in human plasma from subjects with elective coronary artery bypass grafting (cardiovascular risk group, n=27) and a control group (n=27).
RESULTS
MSI identified 362 local metabolic alterations in atherosclerotic mice (log2 fold-change ≥1.5; ≤0.05). The lipid composition of cardiac tissue is altered during atherosclerosis development and presents a generalized accumulation of glycerophospholipids, except for lysolipids. Lysolipids (among other glycerophospholipids) were found at elevated levels in all 3 arterial layers of atherosclerotic aortas. LPC(18:0) (lysophosphatidylcholine; =0.024) and LPA(18:1) (lysophosphatidic acid; =0.025) were found to be significantly elevated in advanced plaques as compared with mouse-matched early plaques. Higher levels of both lipid species were also observed in fibrosis-rich areas of advanced- versus early-stage human samples. They were found to be significantly reduced in human plasma from subjects with elective coronary artery bypass grafting (<0.001 and =0.031, respectively), with LPC(18:0) showing significant association with cardiovascular risk (odds ratio, 0.479 [95% CI, 0.225-0.883]; =0.032) and diagnostic potential (area under the curve, 0.778 [95% CI, 0.638-0.917]).
CONCLUSIONS
An altered phospholipid metabolism occurs in atherosclerosis, affecting both the aorta and the adjacent heart tissue. Plaque-progression lipids LPC(18:0) and LPA(18:1), as identified by MSI on tissue, reflect cardiovascular risk in human plasma.
Topics: Humans; Animals; Mice; Plaque, Atherosclerotic; Cardiovascular Diseases; Risk Factors; Atherosclerosis; Aorta; Aortic Diseases; Glycerophospholipids; Heart Disease Risk Factors
PubMed: 38299357
DOI: 10.1161/ATVBAHA.123.320278