RESUMO
The arterial wall's tri-layered macroscopic and layer-specific microscopic structure determine its mechanical properties, which vary at different arterial locations. Combining layer-specific mechanical data and tri-layered modelling, this study aimed to characterise functional differences between the pig ascending (AA) and lower thoracic aorta (LTA). AA and LTA segments were obtained for n=9 pigs. For each location, circumferentially and axially oriented intact wall and isolated layer strips were tested uniaxially and the layer-specific mechanical response modelled using a hyperelastic strain energy function. Then, layer-specific constitutive relations and intact wall mechanical data were combined to develop a tri-layered model of an AA and LTA cylindrical vessel, accounting for the layer-specific residual stresses. AA and LTA behaviours were then characterised for in vivo pressure ranges while stretched axially to in vivo length. The media dominated the AA response, bearing>2/3 of the circumferential load both at physiological (100 mmHg) and hypertensive pressures (160 mmHg). The LTA media bore most of the circumferential load at physiological pressure only (57±7% at 100 mmHg), while adventitia and media load bearings were comparable at 160 mmHg. Furthermore, increased axial elongation affected the media/adventitia load-bearing only at the LTA. The pig AA and LTA presented strong functional differences, likely reflecting their different roles in the circulation. The media-dominated compliant and anisotropic AA stores large amounts of elastic energy in response to both circumferential and axial deformations, which maximises diastolic recoiling function. This function is reduced at the LTA, where the adventitia shields the artery against supra-physiological circumferential and axial loads.
Assuntos
Túnica Adventícia , Aorta Torácica , Suínos , Animais , Aorta Torácica/fisiologia , Estresse Mecânico , Fenômenos Biomecânicos , Túnica Adventícia/fisiologiaRESUMO
The adventitia receives input signals from the vessel wall, the immune system, perivascular nerves and from surrounding tissues to generate effector responses that regulate structural and mechanical properties of blood vessels. It is a complex and dynamic tissue that orchestrates multiple functions for vascular development, homeostasis, repair, and disease. The purpose of this review is to highlight recent advances in our understanding of the origins, phenotypes, and functions of adventitial and perivascular cells with particular emphasis on hypertensive vascular remodeling.
Assuntos
Túnica Adventícia , Hipertensão , Humanos , Túnica Adventícia/fisiologia , ArtériasRESUMO
We analyze the residual stresses and mechanical properties of layer-dissected infrarenal abdominal aorta (IAA). We measured the axial pre-stretch and opening angle and performed uniaxial tests to study and compare the mechanical behavior of both intact and layer-dissected porcine IAA samples under physiological loads. Finally, some of the most popular anisotropic hyperelastic constitutive models (GOH and microfiber models) were proposed to estimate the mechanical properties of the abdominal aorta by least-square fitting of the recorded in-vitro uniaxial test results. The results show that the residual stresses are layer dependent. In all cases, we found that the OA in the media layer is lower than in the whole artery, the intima and the adventitia. For the axial pre-stretch, we found that the adventitia and the media were slightly stretched in the environment of the intact arterial strip, whereas the intima appears to be compressed. Regarding the mechanical properties, the media seems to be the softest layer over the whole deformation domain showing high anisotropy, while the intima and adventitia exhibit considerable stiffness and a lower anisotropy response. Finally, all the hyperelastic anisotropic models considered in this study provided a reasonable approximation of the experimental data. The GOH model showed the best fitting.
Assuntos
Túnica Adventícia , Aorta Abdominal , Túnica Adventícia/fisiologia , Animais , Anisotropia , Fenômenos Biomecânicos , Estresse Mecânico , SuínosRESUMO
The objective is to know the stress distributions in the arterial walls under residual stresses based on two-layer model. Human common carotid arteries were analysed to show stress distributions at physiological and supraphysiological intraluminal pressures. The analyses for the loaded states were performed with stretch ratios with reference to a Riemannian stress-free configuration which is a 3D non-Euclidean manifold due to the nonzero Riemann curvature tensor. The experimental data obtained by other literature were used for the common carotid arteries to analyse the stretch and stress distributions in the arterial wall although kinematics is different from the literature. The stretches and stresses were calculated for the unloaded state, i.e. the residual stretches and stresses. And those at the axial stretch ratio 1.1 with reference to the unloaded state were calculated at the intraluminal pressures 16, 50, and 100 kPa. The stresses increased from the inner surface to the outer surface at all pressures analysed. These results suggest that in the human arteries the mechanical loads are mainly supported with the adventitia even though the media and intima play an important role to control of physiological functions.
Assuntos
Túnica Adventícia , Artéria Carótida Primitiva , Túnica Adventícia/fisiologia , Fenômenos Biomecânicos/fisiologia , Humanos , Modelos Cardiovasculares , Pressão , Estresse MecânicoRESUMO
Interstitial fluid (ISF) flow through vascular adventitia has been discovered recently. However, its kinetic pattern was unclear. We used histological and topographical identification to observe ISF flow along venous vessels in rabbits. By magnetic resonance imaging (MRI) in live subjects, the inherent pathways of ISF flow from the ankle dermis through the legs, abdomen, and thorax were enhanced by paramagnetic contrast. By fluorescence stereomicroscopy and layer-by-layer dissection after the rabbits were sacrificed, the perivascular and adventitial connective tissues (PACTs) along the saphenous veins and inferior vena cava were found to be stained by sodium fluorescein from the ankle dermis, which coincided with the findings by MRI. The direction of ISF transport in a venous PACT pathway was the same as that of venous blood flow. By confocal microscopy and histological analysis, the stained PACT pathways were verified to be the fibrous connective tissues, consisting of longitudinally assembled fibers. Real-time observations by fluorescence stereomicroscopy revealed at least two types of spaces for ISF flow: one along adventitial fibers and another one between the vascular adventitia and its covering fascia. Using nanoparticles and surfactants, a PACT pathway was found to be accessible by a nanoparticle of <100 nm and contained two parts: a transport channel and an absorptive part. The calculated velocity of continuous ISF flow along fibers of the PACT pathway was 3.6â15.6 mm/s. These data revealed that a PACT pathway was a "slit-shaped" porous biomaterial, comprising a longitudinal transport channel and an absorptive part for imbibition. The use of surfactants suggested that interfacial tension might play an essential role in layers of continuous ISF flow along vascular vessels. A hypothetical "gel pump" is proposed based on interfacial tension and interactions to regulate ISF flow. These experimental findings may inspire future studies to explore the physiological and pathophysiological functions of vascular ISF or interfacial fluid flow among interstitial connective tissues throughout the body.
Assuntos
Túnica Adventícia/fisiologia , Líquido Extracelular/fisiologia , Animais , Transporte Biológico , Vasos Linfáticos/fisiologia , Imageamento por Ressonância Magnética , CoelhosRESUMO
In 1987, Seymour Glagov observed that arteries went through a two-stage remodeling process as a result of plaque growth: first, a compensatory phase where the lumen area remains approximately constant and second, an encroachment phase where the lumen area decreases over time. In this paper, we investigate the effect of growth anisotropy on Glagov remodeling in five different cases: pure radial, pure circumferential, pure axial, isotropic and general anisotropic growth where the elements of the growth tensor are chosen to minimize the total energy. We suggest that the nature of anisotropy is inclined towards the growth direction that requires the least amount of energy. Our framework is the theory of morphoelasticity on an axisymmetric arterial domain. For each case, we explore their specific effect on the Glagov curves. For the latter two cases, we also provide the changes in collagen fiber orientation and length in the intima, media and adventitia. In addition, we compare the total energy produced by growth in radial, circumferential and axial direction and deduce that using a radially dominant anisotropic growth leads to lower strain energy than isotropic growth.
Assuntos
Aterosclerose/etiologia , Modelos Cardiovasculares , Remodelação Vascular/fisiologia , Túnica Adventícia/fisiologia , Túnica Adventícia/fisiopatologia , Artérias/patologia , Artérias/fisiopatologia , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Fenômenos Biomecânicos , Colágeno/metabolismo , Elasticidade , Hemodinâmica/fisiologia , Humanos , Conceitos Matemáticos , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/patologia , Placa Aterosclerótica/fisiopatologia , Túnica Íntima/patologia , Túnica Íntima/fisiopatologia , Túnica Média/patologia , Túnica Média/fisiopatologiaRESUMO
Aortic aneurysm refers to dilatation of the aorta due to loss of elasticity and degenerative weakening of its wall. A preventive role for osteoprotegerin (Opg) in the development of abdominal aortic aneurysm has been reported in the CaCl2-induced aneurysm model, whereas Opg was found to promote suprarenal aortic aneurysm in the AngII-induced ApoE knockout mouse aneurysm model. To determine whether there is a common underlying mechanism to explain the impact of Opg deficiency on the vascular structure of the two aneurysm models, we analyzed suprarenal aortic tissue of 6-month-old ApoE-/-Opg-/- mice after AngII infusion for 28 days. Less aortic dissection and aortic lumen dilatation, more adventitial thickening, and higher expression of collagen I and Trail were observed in ApoE-/-Opg-/- mice relative to ApoE-/-Opg+/+ mice. An accumulation of α-smooth muscle actin and vimentin double-positive myofibroblasts was noted in the thickened adventitia of ApoE-/-Opg-/- mice. Our results suggest that fibrotic remodeling of the aorta induced by myofibroblast accumulation might be an important pathological event which tends to limit AngII-induced aortic dilatation in ApoE -/-Opg-/- mice.
Assuntos
Túnica Adventícia/patologia , Aneurisma da Aorta Abdominal/patologia , Osteoprotegerina/genética , Túnica Adventícia/fisiologia , Angiotensina II/farmacologia , Animais , Aorta Abdominal/patologia , Aorta Abdominal/fisiologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Colesterol/sangue , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fibrose , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miofibroblastos/citologia , Miofibroblastos/metabolismo , Osteoprotegerina/deficiência , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
INTRODUCTION: Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown. METHODS AND RESULTS: The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1α expressions were obviously increased, and SDF-1α levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1α/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and α-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1α expressions in VSMCs by activating PI3K/AKT and NF-κB, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells' differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and α-SMA. CONCLUSIONS: S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1α by activating PI3K/AKT and NF-κB.
Assuntos
Ataxina-1/metabolismo , Lesões das Artérias Carótidas/metabolismo , Mioblastos/metabolismo , Miócitos de Músculo Liso/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Túnica Adventícia/citologia , Túnica Adventícia/fisiologia , Animais , Ataxina-1/genética , Lesões das Artérias Carótidas/patologia , Células Cultivadas , Humanos , Músculo Liso Vascular/citologia , Mioblastos/citologia , Miócitos de Músculo Liso/citologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Regeneração , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Túnica Íntima/citologia , Túnica Íntima/fisiologiaRESUMO
Information on the layer-specific residual deformations of aortic tissue and how these vary throughout the vessel is important for understanding the regionally-varying aortic functions and pathophysiology, but not so much can be found in the literature. Toward this end, porcine aortas were sectioned into eighteen rings, with one ring from each anatomical position radially cut to obtain the zero-stress state for the intact wall and the other ring dissected into intimal-medial and adventitial layers; these rings were then radially cut to reach the zero-stress state for the intima-media and adventitia. Peripheral variations in internal/external circumferences, thickness, and opening angle of the intact wall and its layers were measured through image analysis at the no-load and zero-stress states. Intact wall and layer circumferences at both states significantly declined along the aorta, as did intact wall and intimal-medial but not adventitial thickness. Adventitia exhibited the greatest opening angles, approaching 180â¯deg all over the aorta. The opening angles of the intima-media and intact wall were quite similar, with the highest values in the ascending aorta, the lowest at the diaphragm, and increasing subsequently. Bending-related residual stretches were released by radial cutting that were compressive internally and tensile externally, displaying distinct axial variation for the intima-media and intact wall, and non-significant variation for the adventitia. Evidence is provided for the release upon layer separation of compressive stretches in the intima-media and of tensile stretches in the adventitia, whose values were smallest in the descending thoracic aorta and highest near the iliac artery bifurcation.
Assuntos
Aorta/anatomia & histologia , Fenômenos Mecânicos , Túnica Adventícia/anatomia & histologia , Túnica Adventícia/fisiologia , Animais , Aorta/fisiologia , Fenômenos Biomecânicos , Estresse Mecânico , Suínos , Túnica Íntima/anatomia & histologia , Túnica Íntima/fisiologia , Túnica Média/fisiopatologiaRESUMO
Emerging evidence indicates that fibroblast-specific protein 1 (FSP1) provides vital effects in cell biofunctions. However, whether FSP1 influences the adventitial fibroblast (AF) and vascular remodelling remains unclear. Therefore, we investigated the potential role and action mechanism of FSP1-mediated AF bioactivity. AFs were cultured and stimulated with FSP1 and siRNA-FSP1 in vitro. Viability assays demonstrated that siRNA-FSP1 counteracted AFs proliferative, migratory and adherent abilities enhanced with FSP1. Flow cytometry revealed that FSP1 increased AFs number in S phase and decreased cellular apoptosis. Contrarily, siRNA-FSP1 displayed the contrary results. RT-PCR, Western blotting and immunocytochemistry showed that FSP1 synchronously up-regulated the expression of molecules in RAGE, JAK2/STAT3 and Wnt3a/ß-catenin pathways and induced a proinflammatory cytokine profile characterized by high levels of MCP-1, ICAM-1 and VCAM-1. Conversely, FSP1 knockdown reduced the expression of these molecules and cytokines. The increased number of autophagosomes in FSP1-stimulated group and fewer autophagic corpuscles in siRNA-FSP1 group was observed by transmission electron microscope (TEM). Autophagy-related proteins (LC3B, beclin-1 and Apg7) were higher in FSP1 group than those in other groups. Conversely, the expression of p62 protein was shown an opposite trend of variation. Therefore, these pathways can promote AFs bioactivity, facilitate autophagy and induce the expression of the proinflammatory cytokines. Contrarily, siRNA-FSP1 intercepts the crosstalk of these pathways, suppresses AF functions, restrains autophagy and attenuates the expression of the inflammatory factors. Our findings indicate that crosstalk among RAGE, STAT3/JAK2 and Wnt3a/ß-catenin signalling pathways may account for the mechanism of AF functions with the stimulation of FSP1.
Assuntos
Túnica Adventícia/fisiologia , Antígenos de Neoplasias/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Fibroblastos/fisiologia , Janus Quinase 2/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo , Túnica Adventícia/citologia , Antígenos de Neoplasias/genética , Apoptose , Proteínas de Ligação ao Cálcio/genética , Adesão Celular , Proliferação de Células , Células Cultivadas , Fibroblastos/citologia , Humanos , Janus Quinase 2/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteína A4 de Ligação a Cálcio da Família S100 , Fator de Transcrição STAT3/genética , Transdução de Sinais , Proteína Wnt3A/genética , beta Catenina/genéticaRESUMO
A layer-specific hyperelastic and viscoelastic characterization of human descending thoracic aortas was experimentally performed. Healthy aortas from twelve beating heart donors with an average age of 49.4 years, were received from Transplant Québec. Axial and circumferential strips were prepared from the specimens. They were dissected into intima, media and adventitia layers. Measurements of the opening angles were used to identify the circumferential residual stresses. Uniaxial tensile tests on axial and circumferential strips, together with the Gasser-Ogden-Holzapfel material model, were used to characterize the hyperelastic behaviour of the three aortic layers for each donor. Uniaxial harmonic excitations at different frequency, superimposed to initial stretch values, were used to characterize the viscoelastic behaviour. The storage modulus and the loss tangent were obtained for each layer in both directions; comparison to intact aortic wall was also performed. The generalized Maxwell model, within the framework of nonlinear viscoelasticity with internal variables, was used to obtain the constitutive material parameters. Results showed a positive correlation (pâ¯<â¯0.05 for circumferential media and adventitia) between stiffness and donor age for the three layers of the aorta in both axial and circumferential directions. A significant increase (around 50%) of the storage modulus (i.e. dynamic stiffness) was observed between the quasi-static value and loading at 1â¯Hz frequency, while further increase in frequency marginally affected its value. The loss tangent was only slightly influenced by the stretch value, which justified the use of the viscoelastic model adopted. Finally, similar loss tangent values were found for the three aortic layers.
Assuntos
Aorta Torácica/fisiologia , Elasticidade , Viscosidade , Adulto , Túnica Adventícia/fisiologia , Idoso , Fenômenos Biomecânicos , Feminino , Coração/fisiologia , Humanos , Masculino , Teste de Materiais , Pessoa de Meia-Idade , Pressão , Estresse Mecânico , Resistência à TraçãoRESUMO
Abdominal aortic aneurysm is a prevalent cardiovascular disease with high mortality rates. The mechanical response of the arterial wall relies on the organizational and structural behavior of its microstructural components, and thus, a detailed understanding of the microscopic mechanical response of the arterial wall layers at loads ranging up to rupture is necessary to improve diagnostic techniques and possibly treatments. Following the common notion that adventitia is the ultimate barrier at loads close to rupture, in the present study, a finite element model of adventitial collagen network was developed to study the mechanical state at the fiber level under uniaxial loading. Image stacks of the rabbit carotid adventitial tissue at rest and under uniaxial tension obtained using multi-photon microscopy were used in this study, as well as the force-displacement curves obtained from previously published experiments. Morphological parameters like fiber orientation distribution, waviness, and volume fraction were extracted for one sample from the confocal image stacks. An inverse random sampling approach combined with a random walk algorithm was employed to reconstruct the collagen network for numerical simulation. The model was then verified using experimental stress-stretch curves. The model shows the remarkable capacity of collagen fibers to uncrimp and reorient in the loading direction. These results further show that at high stretches, collagen network behaves in a highly non-affine manner, which was quantified for each sample. A comprehensive parameter study to understand the relationship between structural parameters and their influence on mechanical behavior is presented. Through this study, the model was used to conclude important structure-function relationships that control the mechanical response. Our results also show that at loads close to rupture, the probability of failure occurring at the fiber level is up to 2%. Uncertainties in usually employed rupture risk indicators and the stochastic nature of the event of rupture combined with limited knowledge on the microscopic determinants motivate the development of such an analysis. Moreover, this study will advance the study of coupling microscopic mechanisms to rupture of the artery as a whole.
Assuntos
Túnica Adventícia/fisiologia , Colágenos Fibrilares/química , Modelos Cardiovasculares , Algoritmos , Animais , Fenômenos Biomecânicos , Simulação por Computador , Análise de Elementos Finitos , Masculino , Dinâmica não Linear , Porosidade , Probabilidade , Coelhos , Reprodutibilidade dos Testes , Estresse Mecânico , Resistência à TraçãoRESUMO
The importance of matrix micromechanics is increasingly recognized in cardiovascular research due to the intimate role they play in local vascular cell physiology. However, variations in micromechanics among arterial layers (i.e. intima, media, adventitia), as well as dependency on local matrix composition and/or structure, anatomical location or developmental stage remain largely unknown. This study determined layer-specific stiffness in elastic arteries, including the main pulmonary artery, ascending aorta, and carotid artery using atomic force indentation. To compare stiffness with age and frozen processing techniques, neonatal and adult pulmonary arteries were tested, while fresh (vibratomed) and frozen (cryotomed) tissues were tested from the adult aorta. Results revealed that the mean compressive modulus varied among the intima, sub-luminal media, inner-middle media, and adventitia layers in the range of 1-10â¯kPa for adult arteries. Adult samples, when compared to neonatal pulmonary arteries, exhibited increased stiffness in all layers except adventitia. Compared to freshly isolated samples, frozen preparation yielded small stiffness increases in each layer to varied degrees, thus inaccurately representing physiological stiffness. To interpret micromechanics measurements, composition and structure analyses of structural matrix proteins were conducted with histology and multiphoton imaging modalities including second harmonic generation and two-photon fluorescence. Composition analysis of matrix protein area density demonstrated that decrease in the elastin-to-collagen and/or glycosaminoglycan-to-collagen ratios corresponded to stiffness increases in identical layers among different types of arteries. However, composition analysis was insufficient to interpret stiffness variations between layers which had dissimilar microstructure. Detailed microstructure analyses may contribute to more complete understanding of arterial micromechanics.
Assuntos
Envelhecimento/fisiologia , Artérias/anatomia & histologia , Artérias/fisiologia , Túnica Adventícia/anatomia & histologia , Túnica Adventícia/fisiologia , Animais , Bovinos , Colágeno/metabolismo , Elasticidade , Elastina/metabolismo , Glicosaminoglicanos/metabolismo , Pressão , Túnica Íntima/fisiologiaRESUMO
AIMS: Vascular adventitial fibroblasts (AFs) in the vascular remodeling during atherosclerosis are increasing arousing attention. Acid sphingomyelinase (ASM) is a soluble glycoprotein which is involved in the development and progression of atherosclerosis. However, it remains unknown if ASM is expressed in vascular AFs and regulates vascular adventitial remodeling and underlying mechanisms. MAIN METHODS AND KEY FINDINGS: ASM downregulation with gene silencing was used in the rat AFs treated with angiotensin (Ang) II, which is universally demonstrated to induce vascular adventitia remodeling. It was showed that ASM was indeed expressed in vascular AFs and ASM downregulation resulted in a significant decrease in the protein level of PCNA and collagen I and cell migration under Ang II stimulation. Such improvement of adventitial remodeling was not further augmented by Ang-(1-7), which is deemed as an endogenous Ang II blocker. We further found that ASM downregulation blocked the Nox2-dependent superoxide (O2-) generation, which regulated vascular remodeling in AFs under Ang II. ASM siRNA decreased the aggregation of membrane rafts (MRs) and the consequent recruiting of ceramide and Nox2 in MRs. SIGNIFICANCE: In conclusion, these results suggested that ASM downregulation could improve vascular adventitial remodeling which was attributed to inhibiting MRs/Nox2 redox signaling pathway in AFs. Thus, these data supported the idea that ASM is a potential therapeutic target for diabetic vascular complication.
Assuntos
Angiotensina II/farmacologia , Microdomínios da Membrana/metabolismo , NADPH Oxidase 2/metabolismo , Transdução de Sinais , Esfingomielina Fosfodiesterase/fisiologia , Remodelação Vascular/efeitos dos fármacos , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/metabolismo , Túnica Adventícia/fisiologia , Animais , Western Blotting , Inativação Gênica , Imunoprecipitação , Masculino , Microscopia Confocal , NADPH Oxidase 2/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Esfingomielina Fosfodiesterase/metabolismo , Remodelação Vascular/fisiologiaRESUMO
Migration of vascular smooth muscle cells (VSMCs) is pivotal for vascular remodeling in hypertension. Vascular adventitial fibroblasts (AFs) are important in the homeostasis of vascular structure. This study is designed to investigate the roles of AF exosomes (AFE) in VSMC migration and underling mechanism. Primary VSMCs and AFs were obtained from the aorta of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. VSMC migration was evaluated with Boyden chamber assay and wound healing assay. AFE from WKY rats and SHR were isolated and identified. AFE from SHR promoted but AFE from WKY rats had no significant effect on VSMC migration. The effects of AFE on VSMC migration were prevented by an exosome inhibitor GW4869, an AT1R (Ang II [angiotensin II] type 1 receptor) antagonist losartan, or an inhibitor of ACE (angiotensin-converting enzyme) captopril. ACE contents and activity were much higher in AFE from SHR than those from WKY rats. There were no significant difference in Ang II and AT1R mRNA and protein levels between AFE from SHR and AFE from WKY rats. AFE from SHR increased Ang II and ACE contents and ACE activity in VSMCs of WKY rats and SHR. The changes of Ang II contents and ACE activity were prevented by captopril. ACE knockdown in AFs reduced ACE contents and activity in AFE from SHR and inhibited AFE-induced migration of VSMCs of WKY rats and those of SHR. These results indicate that exosomes from AFs of SHR transfer ACE to VSMCs, which increases Ang II levels and activates AT1R in VSMCs and thereby promotes VSMC migration.
Assuntos
Túnica Adventícia , Exossomos , Fibroblastos , Hipertensão , Peptidil Dipeptidase A , Remodelação Vascular , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/fisiologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Compostos de Anilina/farmacologia , Animais , Compostos de Benzilideno/farmacologia , Captopril/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Técnicas de Silenciamento de Genes/métodos , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Losartan/farmacologia , Músculo Liso Vascular/fisiologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologiaRESUMO
Thoracic aortic dissections involving the ascending aorta represent one of the most dramatic and lethal emergencies in cardiovascular surgery. It is therefore critical to identify the mechanisms driving them and biomechanical analyses hold great clinical promise, since rupture/dissection occur when aortic wall strength is unable to withstand hemodynamic stresses. Although several studies have been done on the biomechanical properties of thoracic aortic aneurysms, few data are available about thoracic aortic dissections. Detailed mechanical tests with measurement of tissue thickness and failure properties were performed with a tensile-testing device on 445 standardized specimens, corresponding to 19 measurement sites per inner (intima with most of media)/outer layer (leftover media with adventitia); harvested from twelve patients undergoing emergent surgical repair for type A dissection. Our data suggested inherent differences in tissue properties between the origin of dissection and distal locations, i.e. thinner and stiffer inner layers that might render them more vulnerable to tearing despite their increased strength. The strength of tissue circumferentially was greater than that longitudinally, likely determining the direction of tear. The relative strengths of the inner: â¼{65,40}N/cm2 and outer layer: â¼{350,270}N/cm2 in the two principal directions of dissected tissue were differentiated from the intima: â¼{100,75}N/cm2, media: â¼{150,55}N/cm2, and adventitia: â¼{270,190}N/cm2 of non-dissected ascending aortic aneurysms (Sokolis et al., 2012), in favor of weaker inner and stronger outer layers, allowing an explanation as to why the presently-studied tissue suffered dissection, i.e. tear of the inner layers, and not rupture, i.e. full tearing across the entire wall thickness.
Assuntos
Aorta/fisiopatologia , Aneurisma da Aorta Torácica/fisiopatologia , Dissecção Aórtica/fisiopatologia , Adulto , Túnica Adventícia/fisiologia , Idoso , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Mecânico , Resistência à Tração , Túnica Íntima/fisiologiaRESUMO
As an important site for the production, storage and release of key regulators for vascular function, the vascular adventitia is thought to be a damage sensing tissue in the vascular wall under certain conditions. The adventitial cells are usually the first ones to respond to vascular stress or injury, and consequently affect the structure and function of blood vessel wall. Growing lines of evidence have shown that the vascular adventitia exhibits the earliest and most prominent changes in vascular remodeling due to hypoxia and related pulmonary hypertension and atherosclerosis. In particular, fibroblasts play an important role in the adaptation and regulation to local microenvironmental changes. This review focuses on the role of vascular adventitia in hypoxia-induced vascular remodeling and the underlying molecular mechanisms.
Assuntos
Túnica Adventícia/fisiologia , Fibroblastos/fisiologia , Hipóxia/fisiopatologia , Remodelação Vascular , Animais , Aterosclerose , Humanos , Hipertensão PulmonarRESUMO
A coupled agent-based model (ABM) and finite element analysis (FEA) computational framework is developed to study the interplay of bio-chemo-mechanical factors in blood vessels and their role in maintaining homeostasis. The agent-based model implements the power of REPAST Simphony libraries and adapts its environment for biological simulations. Coupling a continuum-level model (FEA) to a cellular-level model (ABM) has enabled this computational framework to capture the response of blood vessels to increased or decreased levels of growth factors, proteases and other signaling molecules (on the micro scale) as well as altered blood pressure. Performance of the model is assessed by simulating porcine left anterior descending artery under normotensive conditions and transient increases in blood pressure and by analyzing sensitivity of the model to variations in the rule parameters of the ABM. These simulations proved that the model is stable under normotensive conditions and can recover from transient increases in blood pressure. Sensitivity studies revealed that the model is most sensitive to variations in the concentration of growth factors that affect cellular proliferation and regulate extracellular matrix composition (mainly collagen).
Assuntos
Artérias/crescimento & desenvolvimento , Modelos Cardiovasculares , Remodelação Vascular , Túnica Adventícia/fisiologia , Animais , Fenômenos Biomecânicos , Pressão Sanguínea , Matriz Extracelular/metabolismo , Análise de Elementos Finitos , Camundongos , Estresse Mecânico , Sus scrofa , Análise de Sistemas , Interface Usuário-ComputadorRESUMO
BACKGROUND: Cyclin-dependent kinase inhibitor 1B (p27Kip1) is a cell-cycle inhibitor whose -838C>A single nucleotide polymorphism (rs36228499; hereafter called p27 SNP) has been associated with the clinical failure of peripheral vein grafts, but the functional effects of this SNP have not been demonstrated. METHODS: Human saphenous vein adventitial cells and intimal/medial smooth muscle cells (SMCs) were derived from explants obtained at the time of lower extremity bypass operations. We determined the following in adventitial cells and SMCs as a function of the p27 SNP genotype: (1) p27 promoter activity, (2) p27 messenger (m)RNA and protein levels, and (3) growth and collagen gel contraction. Deoxyribonuclease I footprinting was also performed in adventitial cells and SMCs. RESULTS: p27 promoter activity, deoxyribonuclease I footprinting, p27 mRNA levels, and p27 protein levels demonstrated that the p27 SNP is functional in adventitial cells and SMCs. Both cell types with the graft failure protective AA genotype had more p27 mRNA and protein. As predicted because of higher levels of p27 protein, adventitial cells with the AA genotype grew slower than those of the CC genotype. Unexpectedly, SMCs did not show this genotype-dependent growth response. CONCLUSIONS: These results support the functionality of the p27 SNP in venous SMCs and adventitial cells, but an effect of the SNP on cell proliferation is limited to only adventitial cells. These data point to a potential role for adventitial cells in human vein graft failure and also suggest that SMCs express factors that interfere with the activity of p27.
Assuntos
Túnica Adventícia/fisiologia , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Rejeição de Enxerto/genética , Miócitos de Músculo Liso/fisiologia , Veia Safena/transplante , Enxerto Vascular/efeitos adversos , Túnica Adventícia/citologia , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/metabolismo , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Veia Safena/citologia , Túnica Íntima/citologia , Túnica Íntima/fisiologiaRESUMO
Finite element (FE) simulations are increasingly valuable in assessing and improving the performance of biomedical devices and procedures. Due to high computational demands such simulations may become difficult or even infeasible, especially when considering nearly incompressible and anisotropic material models prevalent in analyses of soft tissues. Implementations of GPGPU-based explicit FEs predominantly cover isotropic materials, e.g. the neo-Hookean model. To elucidate the computational expense of anisotropic materials, we implement the Gasser-Ogden-Holzapfel dispersed, fiber-reinforced model and compare solution times against the neo-Hookean model. Implementations of GPGPU-based explicit FEs conventionally rely on single-point (under) integration. To elucidate the expense of full and selective-reduced integration (more reliable) we implement both and compare corresponding solution times against those generated using underintegration. To better understand the advancement of hardware, we compare results generated using representative Nvidia GPGPUs from three recent generations: Fermi (C2075), Kepler (K20c), and Maxwell (GTX980). We explore scaling by solving the same boundary value problem (an extension-inflation test on a segment of human aorta) with progressively larger FE meshes. Our results demonstrate substantial improvements in simulation speeds relative to two benchmark FE codes (up to 300[Formula: see text] while maintaining accuracy), and thus open many avenues to novel applications in biomechanics and medicine.