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1.
Am J Pathol ; 190(3): 520-534, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31866347

RESUMO

The adventitia, the outer layer of the blood vessel wall, may be the most complex layer of the wall and may be the master regulator of wall physiology and pathobiology. This review proposes a major shift in thinking to apply a functional lens to the adventitia rather than only a structural lens. Human and experimental in vivo and in vitro studies show that the adventitia is a dynamic microenvironment in which adventitial and perivascular adipose tissue cells initiate and regulate important vascular functions in disease, especially intimal hyperplasia and atherosclerosis. Although well away from the blood-wall interface, where much pathology has been identified, the adventitia has a profound influence on the population of intimal and medial endothelial, macrophage, and smooth muscle cell function. Vascular injury and dysfunction of the perivascular adipose tissue promote expansion of the vasa vasorum, activation of fibroblasts, and differentiation of myofibroblasts. This regulates further biologic processes, including fibroblast and myofibroblast migration and proliferation, inflammation, immunity, stem cell activation and regulation, extracellular matrix remodeling, and angiogenesis. A debate exists as to whether the adventitia initiates disease or is just an important participant. We describe a mechanistic model of adventitial function that brings together current knowledge and guides the design of future investigations to test specific hypotheses on adventitial pathobiology.


Assuntos
Aterosclerose/patologia , Hiperplasia/patologia , Doenças Vasculares/patologia , Tecido Adiposo/patologia , Túnica Adventícia/patologia , Matriz Extracelular/patologia , Fibroblastos/patologia , Humanos , Inflamação/patologia , Macrófagos/patologia , Modelos Biológicos , Miócitos de Músculo Liso/patologia , Miofibroblastos/patologia , Células-Tronco/fisiologia , Vasa Vasorum/patologia
2.
Forensic Sci Med Pathol ; 15(4): 591-594, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446611

RESUMO

The body of a 43-year-old African woman with a history of aortic aneurysm and hypertension was forensically investigated after her sudden death. The cause of death was related to a cardiac tamponade due to a ruptured aneurysm of the ascending aorta. Post-mortem gross examination showed an abnormal whitish discoloration of the intima with fibrous thickening of the aortic wall. Several arteries (left main and circumflex coronaries, carotid, renal and iliac arteries) showed similar features. Upon histological examination, the aortic aneurysm as well as the other arteries sampled showed mucoid degeneration, excess mucopolysaccharides and pools of mucin inside the intima and the media associated with collagen and elastic fiber destruction and loss of smooth muscle cells. This pattern strongly suggested the diagnosis of intimomedial mucoid degeneration (IMMD), a rare arterial disorder consisting of a progressive deposition of mucin into the intima and media, with a strong prevalence in middle-aged black African females with high blood pressure. In addition to the typical features of IMMD, histological examination of the ascending aorta showed a thickening of the adventita with sparse mixed inflammatory infiltrates and fibrosis, suggesting an additional chronic infectious aortitis. No infectious agent was detected. The body of literature on IMMD is reviewed and the origin of death is discussed in this case report.


Assuntos
Aorta/patologia , Aneurisma Aórtico/patologia , Glicosaminoglicanos/metabolismo , Mucinas/metabolismo , Túnica Íntima/patologia , Túnica Média/patologia , Adulto , Túnica Adventícia/patologia , Grupo com Ancestrais do Continente Africano , Vasos Coronários/patologia , Morte Súbita/etiologia , Feminino , Fibrose/patologia , Patologia Legal , Humanos , Hipertensão/complicações , Túnica Íntima/metabolismo , Túnica Média/metabolismo
3.
Front Immunol ; 10: 83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30761147

RESUMO

Giant cell arteritis (GCA) can be classified into Cranial(C)-GCA and Large Vessel(LV)-GCA. Based on analysis of temporal arteries, GCA is postulated to be T-cell-mediated. Recently, a disturbed B-cell homeostasis was documented in newly diagnosed GCA patients. In the current study, we assessed the presence of B-cells and their level of ectopic organization in the aorta of LV-GCA patients. Aorta tissue samples of 9 histologically-proven LV-GCA patients and 22 age- and sex-matched atherosclerosis patients who underwent aortic aneurysm surgery were studied by immunohistochemistry. Sections were stained for B-cells, T-cells, follicular dendritic cells, high endothelial venules, germinal center B-cells, proliferating B-cells, macrophages, and plasma cells. Aortas of LV-GCA patients showed massive infiltration of B-cells, which clearly outnumbered T-cells, as opposed to C-GCA patients where, as previously reported, T-cells outnumber B-cells. B-cells were mainly found in the adventitia of the vessel wall and were organized into artery tertiary lymphoid organs. These tertiary lymphoid organs had germinal centers, proliferating B-cells and plasma cell niches. In conclusion, we found massive and organized B-cell infiltrates in the aorta of LV-GCA patients, which is in line with the previously documented decrease of circulating B-cells in active GCA. Our data indicate a role for B-cells in the pathogenesis of GCA and thus evoke further investigation into the factors determining the tissue tropism and organization of B-cells in GCA.


Assuntos
Aorta/patologia , Aterosclerose/patologia , Linfócitos B/patologia , Arterite de Células Gigantes/patologia , Artérias Temporais/patologia , Estruturas Linfoides Terciárias/fisiopatologia , Túnica Adventícia/patologia , Idoso , Aneurisma Aórtico/cirurgia , Linfócitos B/metabolismo , Proliferação de Células , Feminino , Centro Germinativo/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Plasmócitos/patologia , Estudos Retrospectivos , Linfócitos T/patologia
4.
Rheumatology (Oxford) ; 58(4): 609-616, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30517710

RESUMO

OBJECTIVE: To evaluate the influence of disease-related findings and treatment outcomes on survival in a population-based cohort of Northern Italian patients with GCA. METHODS: A total of 281 patients with incident temporal artery biopsy (TAB)-proven GCA, diagnosed over a 26-year period (1986-2012) and living in the Reggio Emilia area, were retrospectively evaluated. We analysed clinical, imaging and laboratory findings at diagnosis, pathological patterns of TAB, CS treatment and therapeutic outcomes, and traditional cardiovascular risk factors as factors predictive of survival. RESULTS: Univariate analysis showed that increased mortality was associated with large vessel involvement at diagnosis [hazard ratio (HR) 5.84], while reduced mortality was associated with female sex (HR 0.66), PMR (HR 0.54), higher haemoglobin levels (HR 0.84) at diagnosis, long-term remission (HR 0.47) and inflammation limited to adventitia or to the adventitial vasa vasorum (HR 0.48) at TAB examination. Multivariate analysis confirmed the association between increased mortality and large vessel involvement (HR 5.14) at diagnosis, between reduced mortality and PMR (HR 0.57) at diagnosis and adventitial inflammation (HR 0.31) at TAB. CONCLUSION: PMR at diagnosis and inflammation limited to the adventitia at TAB appear to identify subsets of patients with more benign disease, while large vessel involvement at diagnosis is associated with reduced survival.


Assuntos
Arterite de Células Gigantes/mortalidade , Adulto , Túnica Adventícia/patologia , Biópsia , Feminino , Arterite de Células Gigantes/patologia , Humanos , Inflamação , Itália , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Artérias Temporais/patologia
5.
Clin Anat ; 32(2): 201-205, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30194877

RESUMO

Volar radial wrist masses are common. Adventitial cysts of the radial artery are rarely reported and poorly understood. We describe a case series of adventitial cysts in association with the radial artery and detail their pathophysiology and treatment. We conducted an Institutional Review Board-approved retrospective review of patients treated at our institution from 1997 to 2018. Twelve patients were identified. Presenting symptoms typically included pain and swelling over the volar radial wrist. High-resolution magnetic resonance imaging (MRI) demonstrated tubular, cystic lesions within the adventitia of the radial artery with connections to the wrist joint confirmed on multiplanar imaging: (radiocarpal joint = 10; scaphotrapeziotrapezoidal joint = 1; and intercarpal joint = 1). Seven patients underwent operation, at which time the cyst was resected and the articular branch disconnected. These patients reported resolution of their symptoms without clinical recurrence. The consistent finding of a joint connection in these cases of adventitial cysts associated with the radial artery has important clinical implications. The joint connection needs to be disconnected. Level of evidence: Level IV, case series. Clin. Anat. 32:201-205, 2019. © 2018 Wiley Periodicals, Inc.


Assuntos
Túnica Adventícia/patologia , Cistos/diagnóstico , Doença Arterial Periférica/diagnóstico , Artéria Radial/patologia , Adolescente , Adulto , Túnica Adventícia/diagnóstico por imagem , Idoso , Cistos/patologia , Cistos/cirurgia , Feminino , Força da Mão , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/cirurgia , Artéria Radial/diagnóstico por imagem , Artéria Radial/cirurgia , Estudos Retrospectivos , Articulação do Punho/diagnóstico por imagem , Adulto Jovem
6.
Stroke ; 49(11): 2767-2769, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30355206

RESUMO

Background and Purpose- Intracranial artery calcification detected by computed tomography is associated with ischemic stroke as an indicator of intracranial atherosclerosis. However, little is known about its histopathology. This study aimed to explore the intracranial calcification patterns and their associations with atherosclerotic plaques. Methods- We recruited 32 adult autopsy cases to assess the calcification patterns and distributions in the middle cerebral artery, vertebral artery, and basilar artery. The relationships of calcification patterns with plaque phenotype and luminal stenosis were evaluated. The calcification patterns on computed tomography were correlated with that on histology. Results- Visible calcifications were detected within 37 (39%) segments, including 25 segments with intimal calcification, 6 segments with internal elastic lamina calcification, 3 segments with adventitial calcification, and 3 segments with concurrent calcification. Calcification occurred more often in the vertebral artery (51%), followed by the middle cerebral artery (35%) and basilar artery (14%; P<0.01 for vertebral artery versus basilar artery). Internal elastic lamina calcification was predominantly detected in the vertebral artery (7/8, 88%). All of the 27 (100%) intimal calcifications were present in the progressive atherosclerotic lesions ( P<0.001), whereas only 3/8 (38%) internal elastic lamina calcifications and 4/6 (67%) adventitial calcifications were associated with progressive plaques. Arteries with intimal calcification had more severe luminal stenosis than those without (46% versus 21%; P<0.001). Conclusions- Our histological findings indicate that the presence of intracranial artery calcification has 3 patterns, including intimal, internal elastic lamina, and adventitial calcifications. But only intimal calcification is related with progressive atherosclerotic lesions, indicative of a proxy for intracranial atherosclerosis.


Assuntos
Artéria Basilar/patologia , Arteriosclerose Intracraniana/patologia , Artéria Cerebral Média/patologia , Calcificação Vascular/patologia , Artéria Vertebral/patologia , Túnica Adventícia/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Artéria Basilar/diagnóstico por imagem , Feminino , Humanos , Doenças Arteriais Intracranianas/diagnóstico por imagem , Doenças Arteriais Intracranianas/patologia , Arteriosclerose Intracraniana/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Túnica Íntima/patologia , Calcificação Vascular/diagnóstico por imagem , Artéria Vertebral/diagnóstico por imagem
7.
Curr Med Sci ; 38(5): 894-902, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30341526

RESUMO

Keloid may induce severe impairment of life quality for the patients, although keloid is a cutaneous benign tumor. Collagen triple helix repeat containing protein 1 (Cthrc1) was identified as a novel gene that was originally found in adventitial fibroblasts after arterial injury. To address the role of Cthrc1 in keloid, the expression level of Cthrc1 was assessed in normal skin and keloid tissue, as well as in normal fibroblasts (NFs) and keloid fibroblasts (KFs) by using quantitative PCR, Western blotting and immunohistochemical analysis. The results showed that Cthrc1 was increased in keloid tissue and KFs as compared with normal skin and NFs. Meanwhile, CCK8 and Transwell assays found the cellular proliferation and migration of KFs were increased as compared with NFs. Further, to verify the function of Cthrc1 in NFs and KFs, we increased Cthrc1 expression by transfecting lentivirus (LV) vectors LV-Cthrc1. The cellular proliferation and migration, collagen synthesis and the influence on TGF-ß and YAP signaling were tested. The cellular proliferation and migration were increased in NFs-Cthrc1 as compared with NFs-control. Meanwhile, YAP expression and nuclear-location was increased in NFs-Cthrc1. On the contrary, when Cthrc1 was overexpressed in KFs, the cellular migration was suppressed and YAP expression was reduced and transferred to cytoplasm in KFs-Cthrc1 as compared with KFs-control. But the expression level of collagen I was decreased and pSmad2/3 nucleus transfer was suppressed in both NFs-Cthrc1 and KFs-Cthrc1 by using Western blotting and immunofluorescence. Increased Cthrc1 activated NFs by promoting YAP nucleus translocation, whereas suppressed KFs by inhibiting YAP nucleus translocation. Enhanced Cthrc1 decreased collagen I in both NFs and KFs by inhibiting TGF-ß/Smad pathway. In conclusion, Cthrc1 may play a role in the pathogenesis of keloid by inhibiting collagen synthesis and fibroblasts migration via suppressing TGF-ß/Smad pathway and YAP nucleus translocation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas da Matriz Extracelular/genética , Queloide/genética , Neoplasias/genética , Fosfoproteínas/genética , Túnica Adventícia/metabolismo , Túnica Adventícia/patologia , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Vetores Genéticos , Humanos , Queloide/metabolismo , Queloide/patologia , Lentivirus/genética , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Smad/genética , Fatores de Transcrição , Transfecção , Fator de Crescimento Transformador beta/genética
9.
Sci Transl Med ; 10(460)2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30257952

RESUMO

Hutchinson-Gilford progeria syndrome is a disorder of premature aging in children caused by de novo mutations in LMNA that lead to the synthesis of an internally truncated form of prelamin A (commonly called progerin). The production of progerin causes multiple disease phenotypes, including an unusual vascular phenotype characterized by the loss of smooth muscle cells in the arterial media and fibrosis of the adventitia. We show that progerin expression, combined with mechanical stress, promotes smooth muscle cell death. Disrupting the linker of the nucleoskeleton and cytoskeleton (LINC) complex in smooth muscle cells ameliorates the toxic effects of progerin on smooth muscle cells and limits the accompanying adventitial fibrosis.


Assuntos
Doenças da Aorta/complicações , Complexos Multiproteicos/metabolismo , Miócitos de Músculo Liso/metabolismo , Progéria/complicações , Progéria/metabolismo , Túnica Adventícia/metabolismo , Túnica Adventícia/patologia , Animais , Aorta/metabolismo , Aorta/patologia , Morte Celular , Células Cultivadas , Colágeno Tipo VIII/biossíntese , Modelos Animais de Doenças , Lamina Tipo A/metabolismo , Lamina Tipo B/metabolismo , Camundongos , Miócitos de Músculo Liso/ultraestrutura , Fenótipo
10.
J Nutr Sci Vitaminol (Tokyo) ; 64(4): 271-276, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175790

RESUMO

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by chronic inflammation in the infrarenal aorta. Epidemiologic data have clearly linked tobacco smoking to aneurysm formation and a faster rate of expansion. It suggested that nicotine, one of the main ingredients of tobacco, has been suggested to be associated with AAA development and rupture. In the condition where no established drugs are available; therefore, an effective approach to prevent the vascular damage from nicotine consumption may be the use of dietary functional food factors. However, little is known about the relationship between dietary components and AAA. In this study, we estimated the effect of dietary deoxyribonucleic acid (DNA) on the vascular wall. After habituation for 5 d, the mice were divided into four groups: control diet and distilled water group (C), DNA-Na diet and distilled water group (DNA), control diet and 0.5 mg/mL nicotine solution group (C-Nic), DNA-Na diet, and 0.5 mg/mL nicotine solution group (DNA-Nic). The dietary DNA attenuated the degradation of elastin fibers induced by nicotine administration. The areas stained positive for MMP-2 in the DNA-Nic group were significantly suppressed compared to C-Nic mice. These data suggest that the dietary DNA may prevent the weakening of the aortic wall via inhibition of the MMP-2-dependent pathway. In conclusion, we have revealed the protective effect of dietary DNA on the vascular pathology of nicotine-administrated mice. A nucleic acid-rich diet might be useful for people who consume nicotine via smoking, chewing tobacco, or nicotine patches.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/prevenção & controle , DNA/uso terapêutico , Suplementos Nutricionais , Modelos Animais de Doenças , Elastina/metabolismo , Endotélio Vascular/metabolismo , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/imunologia , Túnica Adventícia/metabolismo , Túnica Adventícia/patologia , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/imunologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Fármacos Cardiovasculares/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Nicotina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Proteólise/efeitos dos fármacos
11.
Methods Mol Biol ; 1816: 253-268, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29987826

RESUMO

We introduced the vascular remodeling mouse system induced by the wire injury to investigate the molecular and cellular mechanisms of cardiovascular diseases. Using these models, we focus on the adventitial cell population in the outermost layer of the adult vasculature as a vascular progenitor niche. Firstly we used the standard wire injury approach, leaving the wire for 1 min in the artery and retracting the wire by twisting out to expand the artery and denude the inner layer endothelial cells in the both peripheral artery and femoral artery. This method leads to adventitial lineage cell accumulation on the medial-adventitial border, but no contribution into the hyperplastic neointima. Since advanced atherosclerotic plaques in the mouse models and human clinical specimens show the elastic lamina in the media broken, we hypothesized that adventitial lineage cells contribute to acute neointima formation induced by the mechanical damage in both endothelial and medial layers. To make this intensive damage, next, we used the bigger diameter wire with no hydrophilic coating and repeated the ten-times insertion and retraction of the wire after leaving for 1 min in the femoral artery. The additional ten-times intensive movements of the wire lead to breakdown and rupture of the elastic lamina together with a contribution of adventitial lineage cells to the hyperplastic neointima. Here we describe these two different wire injury methods to induce different types of vascular remodeling at the point of adventitial lineage cell contribution to the hyperplastic neointima by targeting two separate locations of hind limb artery, the peripheral artery and femoral artery, and using two different diameter wires.


Assuntos
Túnica Adventícia/patologia , Modelos Animais de Doenças , Artéria Femoral/lesões , Neointima/patologia , Doença Arterial Periférica/patologia , Remodelação Vascular , Túnica Adventícia/citologia , Animais , Células Endoteliais/patologia , Artéria Femoral/patologia , Hiperplasia/etiologia , Hiperplasia/patologia , Camundongos , Neointima/etiologia , Doença Arterial Periférica/etiologia
12.
Diabetes ; 67(8): 1549-1560, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29794241

RESUMO

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.


Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/etiologia , Gordura Intra-Abdominal/metabolismo , Linfocinas/metabolismo , Obesidade/fisiopatologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/imunologia , Túnica Adventícia/metabolismo , Túnica Adventícia/patologia , Angiotensina II/administração & dosagem , Angiotensina II/efeitos adversos , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Benzimidazóis/farmacologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Implantes de Medicamento , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/patologia , Linfocinas/agonistas , Linfocinas/antagonistas & inibidores , Linfocinas/genética , Masculino , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Especificidade de Órgãos , Fator de Crescimento Derivado de Plaquetas/agonistas , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/genética , Quinolinas/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Gordura Subcutânea Abdominal/efeitos dos fármacos , Gordura Subcutânea Abdominal/imunologia , Gordura Subcutânea Abdominal/metabolismo , Gordura Subcutânea Abdominal/patologia , Análise de Sobrevida
13.
Acta Biomater ; 73: 437-448, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29684625

RESUMO

The collagen-rich adventitia is the outermost arterial layer and plays an important biomechanical and physiological role in normal vessel function. While there has been a lot of effort to understand the role of the medial layer on arterial biomechanics, the adventitia has received less attention. In this study, we hypothesized that different ultrastructural and nanomechanical properties would be exhibited in the adventitia of the internal mammary artery (IMA) in patients with a low degree of arterial stiffening as compared to those with a high degree of arterial stiffening. Human IMA biopsies were obtained from a cohort of patients with arterial stiffening assessed via carotid-femoral PWV. Patients were grouped as low PWV (8.5 ±â€¯0.7 ms-1, n = 8) and high PWV (13.4 ±â€¯3.0 ms-1, n = 9). Peakforce QNM atomic force microscopy (AFM) was used to determine the nanomechanical and morphological properties of the IMA. The nano-scale elastic modulus was found to correlate with PWV. We show for the first time that nano-scale alterations in adventitial collagen fibrils in the IMA are evident in patients with high PWV, even though the IMA is not involved in the carotid-femoral pathway. Our approach provides new insight into systemic structure-property changes in the vasculature, and also provides a method of characterizing small biopsy samples to predict the development of arterial stiffening. STATEMENT OF SIGNIFICANCE: Arterial stiffening occurs as part of the natural aging process and is strongly linked to cardiovascular risk. Although arterial stiffening is routinely measured in vivo, little is known about how localised changes in artery structure and biomechanics contributes to in vivo arterial stiffening. This study focusses on the role of the outermost layer of arteries, the adventitia, in arterial stiffening. The study provides data on nano-scale changes in collagen fibril structure and mechanical properties in the adventitia and shows how it relates to in vivo stiffness measurements in the vascular system. This is the first study to link in vivo arterial stiffening with nanomechanical changes in artery biopsy samples. Hence, this approach could be used to develop new diagnostic methods for vascular disease.


Assuntos
Túnica Adventícia/diagnóstico por imagem , Artéria Torácica Interna/diagnóstico por imagem , Análise de Onda de Pulso , Túnica Adventícia/patologia , Idoso , Fenômenos Biomecânicos , Biópsia , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Estudos de Coortes , Colágeno/química , Módulo de Elasticidade , Feminino , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/patologia , Humanos , Masculino , Artéria Torácica Interna/patologia , Microscopia de Força Atômica , Pessoa de Meia-Idade , Modelos Cardiovasculares , Nanomedicina , Análise de Componente Principal , Proteômica , Risco , Doenças Vasculares/diagnóstico , Rigidez Vascular
14.
Interact Cardiovasc Thorac Surg ; 27(3): 427-436, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29617792

RESUMO

OBJECTIVES: Open arterial revascularization using venous segments is frequently associated with the development of intimal hyperplasia (IH), leading to severe restenosis and graft failure. The lack of treatment to prevent this pathology is a major problem. Therefore, we generated a new porcine model, which closely mimics the clinical development of human IH, to test the therapeutic potential of candidate drugs. METHODS: A patch of jugular vein was sutured to the right common carotid artery of pigs, to expose the vein to haemodynamic conditions of the arterial bed. Four weeks after surgery, the operated vessels which received no further treatment (the control group) were compared with (i) contralateral, non-operated vessels (the healthy group); (ii) vessels of pigs that received a perivascular application of a drug-free microparticle gel (the placebo group) and (iii) vessels of pigs that perioperatively received the same gel loaded with 10-mg atorvastatin (the atorvastatin group). RESULTS: When compared with non-operated vessels, all operated segments displayed a sizable IH which was thicker in the venous patch than in the host artery. These alterations were associated with a thickening of the intima layer of both vessels in the absence of inflammation. The intima/media ratio has been significantly increased by 2000-fold in the vein patches. Perivascular application of atorvastatin did not prevent IH formation. However, the drug increased the adventitial neovascularization in the operated vessels. CONCLUSIONS: The novel porcine model allows for monitoring IH formation under haemodynamic conditions which mimic clinical situations. It should facilitate the screening of innovative treatments to prevent restenosis.


Assuntos
Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/cirurgia , Veias Jugulares/patologia , Veias Jugulares/cirurgia , Túnica Íntima/patologia , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/patologia , Animais , Atorvastatina/farmacologia , Artéria Carótida Primitiva/efeitos dos fármacos , Constrição Patológica , Modelos Animais de Doenças , Hemodinâmica , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperplasia , Veias Jugulares/efeitos dos fármacos , Suínos , Túnica Íntima/efeitos dos fármacos , Procedimentos Cirúrgicos Vasculares/efeitos adversos
15.
Cardiovasc Pathol ; 34: 9-14, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29525729

RESUMO

Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections. Subsequent immunohistochemically staining was performed with the following markers: (myeloperoxidase (neutrophils), citrullinated-Histone 3 (neutrophil extracellular traps), CD68 (macrophages), CD3 (T-cells), CD31 and CD34 (endothelial cells), and smooth muscle actin. Immune stained sections were scored semi-quantitatively. Histologically, five cases were identified as stage I, 16 as II, 7 as III and 4 as IV. Additional immunostaining for smooth muscle cells and endothelial cells altered the classification in 25% of cases (all in groups II and III). Immunostaining and semi-quantitative grading of involvement of neutrophils, macrophages and NETs also provided specific distribution patterns over the 4 age categories, including unexpected involvement of the peri adventitial fat tissue. In conclusion, it appears that semi-quantitative immunohistochemistry of resident vascular wall cells, inflammatory cells and NETS represents a useful adjunct in detailed histopathological grading of the chronological age of aortic dissections.


Assuntos
Aneurisma Dissecante/imunologia , Aorta/imunologia , Aneurisma Aórtico/imunologia , Imunofenotipagem/métodos , Túnica Média/imunologia , Remodelação Vascular , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Túnica Adventícia/imunologia , Túnica Adventícia/patologia , Aneurisma Dissecante/patologia , Aorta/patologia , Aneurisma Aórtico/patologia , Biomarcadores/análise , Progressão da Doença , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Imuno-Histoquímica , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Fenótipo , Estudos Retrospectivos , Túnica Média/patologia
18.
Am J Pathol ; 188(4): 838-845, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29341889

RESUMO

Transplant vasculopathy is one of the major causes of chronic rejection after solid organ transplantation. The pathogenic mechanisms of transplant vasculopathy are still poorly understood. Herein, we summarize current evidence suggesting that activation of the tunica adventitia may be involved in the pathogenesis of transplant vasculopathy. Adventitia is an early responder to various vascular injuries and plays an integral role in eliciting vascular inflammation and remodeling. Accumulation of macrophages in the adventitia promotes the development of vascular remodeling by releasing a variety of paracrine factors that have profound impacts on vascular mural cells. Targeting adventitial macrophages has been shown to be effective for repressing transplantation-induced arterial remodeling in animal models. Adventitia also fosters angiogenesis, and neovascularization of the adventitial layer may facilitate the transport of inflammatory cells through the arterial wall. Further investigations are warranted to clarify whether inhibiting adventitial oxidative stress and/or adventitial neovascularization are better strategies for preventing transplant vasculopathy.


Assuntos
Túnica Adventícia/patologia , Artérias/lesões , Artérias/fisiopatologia , Transplante/efeitos adversos , Doenças Vasculares/etiologia , Remodelação Vascular , Animais , Artérias/patologia , Humanos , Estresse Oxidativo , Doenças Vasculares/patologia , Doenças Vasculares/fisiopatologia
19.
Curr Drug Targets ; 19(11): 1327-1332, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29359664

RESUMO

BACKGROUND: An abdominal aortic aneurysm (AAA), which affects approximately 10% of Japanese men aged ≥ 65 years, is frequently associated with hypertension, dyslipidemia, and other lifestyle- related diseases. The development of an AAA is attributed to chronic inflammation concomitant with arteriosclerotic changes. However, an accurate pathomechanism associated with AAA remains uncertain, and questions such as why only a particular group/percentage of patients with arteriosclerosis develop aneurysms and how diabetes suppresses aneurysm development remain unanswered. OBJECTIVE: We examined a novel mechanism to develop AAA based on histopathological findings following analysis of the human AAA tissues. Additionally, based on these findings, we developed a new animal model of AAA, in which the histopathological characteristics are similar to human AAA tissue. RESULTS: Recently, we identified stenosis of the vasa vasorum (VV) in aortic segments showing dilatation. The aorta is the largest artery in our circulatory system. Under physiological conditions, the inner layer of the aorta is nourished via direct diffusion of nutrients from the luminal blood flow, whereas the outer adventitia is primarily perfused by the VV. Therefore, hypoperfusion of the VV induces hypoxia and subsequent inflammation and tissue degeneration of the aortic wall, resulting in aneurysm formation. Based on these findings, we established an AAA animal model by reducing the blood flow through the VV to the aortic wall. AAA was successfully reproduced in our animal model. Histopathological findings in this model were indistinguishable from those observed in humans, and pronounced abnormality in lipid composition in blood vessel adventitia was also observed. CONCLUSION: Thus, hypoperfusion of the aortic wall appeared to be sufficient to cause inflammationinduced AAA. These findings may provide potential targets for novel therapeutics for the management of an AAA.


Assuntos
Túnica Adventícia/patologia , Aneurisma da Aorta Abdominal/patologia , Vasa Vasorum/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Modelos Animais de Doenças , Humanos , Japão , Metabolismo dos Lipídeos , Masculino , Ratos , Projetos de Pesquisa , Vasa Vasorum/imunologia , Vasa Vasorum/metabolismo
20.
J Hypertens ; 36(5): 1104-1114, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29303830

RESUMO

OBJECTIVE: Phenotypic transformation of adventitial fibroblasts is important in the pathogenesis of hypertension. This study was designed to determine whether fibronectin type III domain containing 5 (FNDC5) alleviates the phenotypic transformation of adventitial fibroblasts in hypertension and the underlying mechanisms. METHODS AND RESULTS: Experiments were carried out in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and primary aortic adventitial fibroblasts. FNDC5 was downregulated and NLRP3 inflammasome was activated in aortic adventitia of SHR. FNDC5 overexpression attenuated adventitial fibroblasts phenotypic transformation, excessive synthesis and secretion of matrix components, NLRP3 inflammasome activation and inflammation in adventitial fibroblasts from SHR. Moreover, FNDC5 overexpression reduced NADPH oxidase 2 (NOX2) expression and reactive oxygen species (ROS) production in adventitial fibroblasts from SHR. Similarly, exogenous FNDC5 inhibited adventitial fibroblasts phenotypic transformation, expression of matrix components, NLRP3 inflammasome activation and NOX2 expression in adventitial fibroblasts from SHR. FNDC5 overexpression in rats attenuated phenotypic transformation, inflammation and reactive oxygen species (ROS) production in the aortic adventitia of SHR. Furthermore, FNDC5 overexpression reduced blood pressure and alleviated vascular remodeling in SHR. CONCLUSION: FNDC5 reduces NOX2-derived ROS production, NLRP3 inflammasome activation and phenotypic transformation in adventitial fibroblasts of SHR. FNDC5 plays a beneficial role in attenuating vascular inflammation, vascular remodeling and hypertension in SHR.


Assuntos
Fibroblastos/fisiologia , Fibronectinas/metabolismo , Hipertensão/fisiopatologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Túnica Adventícia/patologia , Animais , Aorta/patologia , Pressão Sanguínea , Matriz Extracelular/metabolismo , Fibroblastos/patologia , Fibronectinas/farmacologia , Inflamassomos/efeitos dos fármacos , Masculino , NADPH Oxidase 2/metabolismo , Fenótipo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , Remodelação Vascular
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