RESUMO
Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-ß/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.
Assuntos
Aorta Torácica/efeitos dos fármacos , Aneurisma da Aorta Torácica/prevenção & controle , Dissecção Aórtica/prevenção & controle , Fibrilina-1/genética , Síndrome de Marfan/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Adulto , Dissecção Aórtica/enzimologia , Dissecção Aórtica/genética , Dissecção Aórtica/patologia , Animais , Aorta Torácica/enzimologia , Aorta Torácica/patologia , Aneurisma da Aorta Torácica/enzimologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Humanos , Masculino , Síndrome de Marfan/complicações , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Proteína Smad3/metabolismoRESUMO
BACKGROUND: Mechanical homeostasis promotes proper aortic structure and function. Pathological conditions may arise, in part, from compromised or lost homeostasis. There is thus a need to quantify the homeostatic state and when it emerges. Here we quantify changes in mechanical loading, geometry, structure, and function of the murine aorta from the late prenatal period into maturity. RESULTS: Our data suggest that a homeostatic set-point is established by postnatal day P2 for the flow-induced shear stress experienced by endothelial cells; this value deviates from its set-point from P10 to P21 due to asynchronous changes in mechanical loading (flow, pressure) and geometry (radius, wall thickness), but is restored thereafter consistent with homeostasis. Smooth muscle contractility also decreases during this period of heightened matrix deposition but is also restored in maturity. The pressure-induced mechanical stress experienced by intramural cells initially remains low despite increasing blood pressure, and then increases while extracellular matrix accumulates. CONCLUSIONS: These findings suggest that cell-level mechanical homeostasis emerges soon after birth to allow mechanosensitive cells to guide aortic development, with deposition of matrix after P2 increasingly stress shielding intramural cells. The associated tissue-level set-points that emerge for intramural stress can be used to assess and model the aorta that matures biomechanically by P56.
Assuntos
Adaptação Biológica , Aorta Torácica/crescimento & desenvolvimento , Animais , Homeostase , Masculino , Camundongos Endogâmicos C57BL , Estresse MecânicoRESUMO
Vascular smooth muscle cells (VSMCs) can regulate arterial mechanics via contractile activity in response to changing mechanical and chemical signals. Contractility is traditionally evaluated via uniaxial isometric testing of isolated rings despite the in vivo environment being very different. Most blood vessels maintain a locally preferred value of in vivo axial stretch while subjected to changes in distending pressure, but both of these phenomena are obscured in uniaxial isometric testing. Few studies have rigorously analyzed the role of in vivo loading conditions in smooth muscle function. Thus, we evaluated effects of uniaxial versus biaxial deformations on smooth muscle contractility by stimulating two regions of the mouse aorta with different vasoconstrictors using one of three testing protocols: (i) uniaxial isometric testing, (ii) biaxial isometric testing, and (iii) axially isometric plus isobaric testing. Comparison of methods (i) and (ii) revealed increased sensitivity and contractile capacity to potassium chloride and phenylephrine (PE) with biaxial isometric testing, and comparison of methods (ii) and (iii) revealed a further increase in contractile capacity with isometric plus isobaric testing. Importantly, regional differences in estimated in vivo axial stretch suggest locally distinct optimal biaxial configurations for achieving maximal smooth muscle contraction, which can only be revealed with biaxial testing. Such differences highlight the importance of considering in vivo loading and geometric configurations when evaluating smooth muscle function. Given the physiologic relevance of axial extension and luminal pressurization, we submit that, when possible, axially isometric plus isobaric testing should be employed to evaluate vascular smooth muscle contractile function.
Assuntos
Contração Isométrica , Teste de Materiais/métodos , Fenômenos Mecânicos , Vasoconstrição , Animais , Fenômenos Biomecânicos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/fisiologiaRESUMO
Vasoconstriction and vasodilation play important roles in the circulatory system and can be regulated through different pathways that depend on myriad biomolecules. These different pathways reflect the various functions of smooth muscle cell (SMC) contractility within the different regions of the arterial tree and how they contribute to both the mechanics and the mechanobiology. Here, we review the primary regulatory pathways involved in SMC contractility and highlight their regional differences in elastic, muscular, and resistance arteries. In this way, one can begin to assess how these properties affect important biomechanical and mechanobiological functions in the circulatory system in health and disease.
Assuntos
Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/citologia , Vasoconstrição , Artérias/fisiologia , Fenômenos Biomecânicos , Humanos , Músculos/fisiologia , VasodilataçãoRESUMO
OBJECTIVE: Transforming growth factor-beta is a pleiotropic cytokine having diverse roles in vascular morphogenesis, homeostasis, and pathogenesis. Altered activity of and signaling through transforming growth factor-beta has been implicated in thoracic aortic aneurysms and dissections, conditions characterized by a reduced structural integrity of the wall that associates with altered biomechanics and mechanobiology. We quantify and contrast the passive and active biaxial biomechanical properties of the ascending and proximal descending thoracic aorta in a mouse model of altered transforming growth factor-beta signaling, with and without treatment with rapamycin. APPROACH AND RESULTS: Postnatal disruption of the gene (Tgfbr2) that codes the type II transforming growth factor-beta receptor compromises vessel-level contractility and elasticity. Daily treatment with rapamycin, a mechanistic target of rapamycin inhibitor that protects against aortic dissection in these mice, largely preserves or restores the contractile function while the passive properties remain compromised. Importantly, this increased smooth muscle contractility protects an otherwise vulnerable aortic wall from pressure-induced intramural delaminations in vitro. CONCLUSIONS: Notwithstanding the protection afforded by rapamycin in vivo and in vitro, the residual mechanical dysfunctionality suggests a need for caution if rapamycin is to be considered as a potential therapeutic. There is a need for in vivo evaluations in cases of increased hemodynamic loading, including hypertension or extreme exercise, which could unduly stress a structurally vulnerable aortic wall. Given these promising early results, however, such studies are clearly warranted.
Assuntos
Aneurisma da Aorta Torácica/prevenção & controle , Dissecção Aórtica/prevenção & controle , Matriz Extracelular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Sirolimo/farmacologia , Rigidez Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Dissecção Aórtica/fisiopatologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/fisiopatologia , Pressão Arterial , Elasticidade , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Predisposição Genética para Doença , Masculino , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Estresse Mecânico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
Physiological loading in large elastic arteries is considered to be mainly carried by the passive components of the media but it is not known how much the contraction of the smooth muscle cells is actually involved in the load carrying. Smooth muscle contraction is considered to occur in a relatively slow time domain but the contraction is able to produce significant tension. In the present work the role of smooth muscle contraction in large elastic arteries is investigated by analyzing how changes in the intracellular calcium, and thereby the active tone of smooth muscle cells, influence the deformation and stress behavior; different intracellular calcium functions and medial wall thicknesses with cycling internal pressure are studied. In particular, a recently proposed mechanochemical model (Murtada et al., 2012. J. Theor. Biol. 297, 176-186), which links intracellular calcium with mechanical contraction and an anisotropic model representing the elastin/collagen composite, was implemented into a 3D finite element framework. Details of the implementation procedure are described and a verification of the model implementation is provided by means of the isometric contraction/relaxation analysis of a medial strip at optimal muscle length. In addition, numerically obtained pressure-radius relationships of arterial rings modeled with one and two layers are analyzed with different geometries and at different calcium levels; a comparison with the Laplace equation is provided. Finally, a two-layer arterial ring is loaded with a realistic pressure wave and with various intracellular calcium functions (different amplitudes and mean values) and medial wall thicknesses; residual stresses are considered. The finite element results show that changes in the calcium amplitudes hardly have an influence on the current inner ring radius and the circumferential stress. However, an increase in the mean intracellular calcium value and the medial wall thickness leads to a clear influence on the deformation and the stress behavior.
Assuntos
Análise de Elementos Finitos , Músculo Liso/citologia , Animais , Camundongos , Contração Muscular , Músculo Liso/fisiologiaRESUMO
The renin-angiotensin system plays a key role in regulating blood pressure, which has motivated many investigations of associated mouse models of hypertensive arterial remodelling. Such studies typically focus on histological and cell biological changes, not wall mechanics. This study explores tissue-level ramifications of chronic angiotensin II infusion in wild-type (WT) and type 1b angiotensin II (AngII) receptor null (Agtr1b -/-) mice. Biaxial biomechanical and immunohistological changes were quantified and compared in the thoracic and abdominal aorta in these mice following 14 and 28 days of angiotensin II infusion. Preliminary results showed that changes were largely independent of sex. Associated thickening and stiffening of the aortic wall in male mice differed significantly between thoracic and abdominal regions and between genotypes. Notwithstanding multiple biomechanical changes in both WT and Agtr1b -/- mice, AngII infusion caused distinctive wall thickening and inflammation in the descending thoracic aorta of WT, but not Agtr1b -/-, mice. Our study underscores the importance of exploring differential roles of receptor-dependent angiotensin II signalling along the aorta and its influence on distinct cell types involved in regional histomechanical remodelling. Disrupting the AT1b receptor primarily affected inflammatory cell responses and smooth muscle contractility, suggesting potential therapeutic targets.
Assuntos
Angiotensina II , Camundongos Knockout , Receptor Tipo 1 de Angiotensina , Remodelação Vascular , Animais , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Camundongos , Masculino , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Feminino , Aorta Torácica/metabolismo , Aorta Torácica/patologiaRESUMO
Despite its vital importance for establishing proper cardiovascular function, the process through which the vasculature develops and matures postnatally remains poorly understood. From a clinical perspective, an ability to mechanistically model the developmental time course in arteries and veins, as well as to predict how various pathologies and therapeutic interventions alter the affected vessels, promises to improve treatment strategies and long-term clinical outcomes, particularly in pediatric patients suffering from congenital heart defects. In the present study, we conducted a multiscale investigation into the postnatal development of the murine thoracic aorta, examining key allometric relations as well as relationships between in vivo mechanical stresses, collagen and elastin expression, and the gradual accumulation of load-bearing constituents within the aortic wall. Our findings suggest that the production of fibrillar collagens in the developing aorta associates strongly with the ratio of circumferential stresses between systole and diastole, hence emphasizing the importance of a pulsatile mechanobiological stimulus. Moreover, rates of collagen turnover and elastic fiber compaction can be inferred directly by synthesizing transcriptional data and quantitative histological measurements of evolving collagen and elastin content. Consistent with previous studies, we also observed that wall shear stresses acting on the aorta are similar at birth and in maturity, supporting the hypothesis that at least some stress targets are established early in development and maintained thereafter, thus providing a possible homeostatic basis to guide future experiments and inform future predictive modeling.
Assuntos
Aorta , Elastina , Recém-Nascido , Humanos , Animais , Camundongos , Criança , Elastina/metabolismo , Aorta Torácica/patologia , Colágeno/metabolismo , Colágenos Fibrilares/metabolismo , Estresse MecânicoRESUMO
Hypertension and transient increases in blood pressure from extreme exertion are risk factors for aortic dissection in patients with age-related vascular degeneration or inherited connective tissue disorders. Yet, the common experimental model of angiotensin II-induced aortopathy in mice appears independent of high blood pressure as lesions do not occur in response to an alternative vasoconstrictor, norepinephrine, and are not prevented by co-treatment with a vasodilator, hydralazine. We investigated vasoconstrictor administration to adult mice 1 week after disruption of TGFß signaling in smooth muscle cells. Norepinephrine increased blood pressure and induced aortic dissection by 7 days and even within 30 minutes that was rescued by hydralazine; results were similar with angiotensin II. Changes in regulatory contractile molecule expression were not of pathological significance. Rather, reduced synthesis of extracellular matrix yielded a vulnerable aortic phenotype by decreasing medial collagen, most dynamically type XVIII, and impairing cell-matrix adhesion. We conclude that transient and sustained increases in blood pressure cause dissection in aortas rendered vulnerable by inhibition of TGFß-driven extracellular matrix production by smooth muscle cells. A corollary is that medial fibrosis, a frequent feature of medial degeneration, may afford some protection against aortic dissection.
RESUMO
Pregnancy associates with dramatic changes in maternal cardiovascular physiology that ensure that the utero-placental circulation can support the developing fetus. Particularly striking is the marked flow-induced remodeling of uterine arteries during pregnancy and their recovery following birth. Whereas details are available in the literature on alterations in hemodynamics within and changes in the dimensions of uterine arteries during and following pregnancy in mice, we report here the first biaxial biomechanical phenotyping of these arteries during this dynamic period of growth and remodeling (G&R). To gain additional insight into the measured G&R, we also use a computational constrained mixture model to describe and predict findings, including simulations related to complications that may arise during pregnancy. It is found that dramatic pregnancy-induced remodeling of the uterine artery is largely, but not completely, reversed in the postpartum period, which appears to be driven by increases in collagen turnover among other intramural changes. By contrast, data on the remodeling of the ascending aorta, an elastic artery, reveal modest changes that are fully recovered postpartum. There is strong motivation to continue biomechanical studies on this critical aspect of women's health, which has heretofore not received appropriate consideration from the biomechanics community.
Assuntos
Placenta , Artéria Uterina , Humanos , Gravidez , Camundongos , Feminino , Animais , Artéria Uterina/fisiologia , Placenta/irrigação sanguínea , Hemodinâmica , Útero/irrigação sanguínea , Circulação PlacentáriaRESUMO
Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end of life. We associate progressive deterioration of arterial structure and function with single cell transcriptional changes, which reveals a rapid disease process in proximal elastic arteries that largely spares distal muscular arteries. These data suggest a novel sequence of progressive vascular disease in progeria: initial extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death in proximal arteries, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotypic modulation that results in an accumulation of proteoglycans that thickens the wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased pulse wave velocity drives left ventricular diastolic dysfunction, the primary diagnosis in progeria children. Mitigating smooth muscle cell loss / phenotypic modulation promises to have important cardiovascular implications in progeria patients.
RESUMO
Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process in proximal elastic arteries that was less evident in distal muscular arteries. Changes in aortic structure and function were then associated with changes in transcriptomics assessed via both bulk and single cell RNA sequencing, which suggested a novel sequence of progressive aortic disease: adverse extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotype that results in an accumulation of proteoglycans that thickens the aortic wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased central artery pulse wave velocity is known to drive left ventricular diastolic dysfunction, the primary diagnosis in progeria children. It appears that mechanical stresses above ~ 80 kPa initiate this progressive aortic disease process, explaining why elastic lamellar structures that are organized early in development under low wall stresses appear to be nearly normal whereas other medial constituents worsen progressively in adulthood. Mitigating early mechanical stress-driven smooth muscle cell loss/phenotypic modulation promises to have important cardiovascular implications in progeria patients.
Assuntos
Doenças da Aorta , Progéria , Criança , Humanos , Progéria/genética , Progéria/metabolismo , Análise de Onda de Pulso , Fenótipo , Doenças da Aorta/metabolismo , Miócitos de Músculo Liso/metabolismoRESUMO
Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.
Assuntos
Progéria , Camundongos , Animais , Progéria/tratamento farmacológico , Progéria/genética , Análise de Onda de Pulso , Piperidinas/farmacologia , Sirolimo/uso terapêutico , Lamina Tipo ARESUMO
To assess the contribution of individual TGF-ß isoforms to aortopathy in Marfan syndrome (MFS), we quantified the survival and phenotypes of mice with a combined fibrillin1 (the gene defective in MFS) hypomorphic mutation and a TGF-ß1, 2, or 3 heterozygous null mutation. The loss of TGF-ß2, and only TGF-ß2, resulted in 80% of the double mutant animals dying earlier, by postnatal day 20, than MFS only mice. Death was not from thoracic aortic rupture, as observed in MFS mice, but was associated with hyperplastic aortic valve leaflets, aortic regurgitation, enlarged aortic root, increased heart weight, and impaired lung alveolar septation. Thus, there appears to be a relationship between loss of fibrillin1 and TGF-ß2 in the postnatal development of the heart, aorta and lungs.
Assuntos
Haploinsuficiência , Síndrome de Marfan , Animais , Camundongos , Aorta , Fibrilina-1/genética , Síndrome de Marfan/genética , Fenótipo , Fator de Crescimento Transformador beta2/genéticaRESUMO
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency leads to cardiovascular calcification in infancy, fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets in childhood, and osteomalacia in adulthood. Excessive enthesis mineralization and cervical spine fusion have been previously reported in patients with biallelic ENPP1 deficiency, but their effect on quality of life is unknown. We describe additional musculoskeletal complications in patients with ENPP1 deficiency, namely osteoarthritis and interosseous membrane ossification, and for the first time evaluate health-related quality of life (HRQoL) in patients with this disease, both subjectively via narrative report, and objectively via the Brief Pain Inventory-Short Form, and a Patient Reported Outcome Measurement Information System Physical Function (PROMIS PF) short form. Residual pain, similar in magnitude to that identified in adult patients with X-linked hypophosphatemia, was experienced by the majority of patients despite use of analgesic medications. Impairment in physical function varied from mild to severe. To assess murine ENPP1 deficiency for the presence of enthesopathy, and for the potential response to enzyme replacement therapy, we maintained Enpp1asj/asj mice on regular chow for 23 weeks and treated cohorts with either vehicle or a long-acting form of recombinant ENPP1. Enpp1asj/asj mice treated with vehicle exhibited robust calcification throughout their Achilles tendons, whereas two-thirds of those treated with ENPP1 enzyme replacement exhibited complete or partial suppression of the Achilles tendon calcification. Our combined results document that musculoskeletal complications are a significant source of morbidity in biallelic ENPP1 deficiency, a phenotype which is closely recapitulated in Enpp1asj/asj mice. Finally, we show that a long-acting form of recombinant ENPP1 prevents the development of enthesis calcification at the relatively modest dose of 0.3 mg/kg per week, suggesting that suppression of enthesopathy may be attainable upon dose escalation. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Assuntos
Entesopatia , Raquitismo Hipofosfatêmico Familiar , Calcificação Vascular , Adulto , Animais , Modelos Animais de Doenças , Entesopatia/tratamento farmacológico , Entesopatia/genética , Terapia de Reposição de Enzimas , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Fatores de Crescimento de Fibroblastos , Humanos , Masculino , Camundongos , Dor , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Qualidade de Vida , Calcificação Vascular/genéticaRESUMO
Vascular complications are a major cause of illness and death in patients with type 1 diabetes (T1D). Diabetic vascular basement membranes are enriched in fibronectin (FN), an extracellular matrix protein that amplifies inflammatory signaling in endothelial cells through its main receptor, integrin α5ß1. Binding of the integrin α5 cytoplasmic domain to phosphodiesterase 4D5 (PDE4D5), which increases phosphodiesterase catalytic activity and inhibits antiinflammatory cAMP signaling, was found to mediate these effects. Here, we examined mice in which the integrin α5 cytoplasmic domain is replaced by that of α2 (integrin α5/2) or the integrin α5 binding site in PDE4D is mutated (PDE4Dmut). T1D was induced via injection of streptozotocin and hyperlipidemia induced via injection of PCSK9 virus and provision of a high-fat diet. We found that in T1D and hyperlipidemia, the integrin α5/2 mutation reduced atherosclerosis plaque size by â¼50%, with reduced inflammatory cell invasion and metalloproteinase expression. Integrin α5/2 T1D mice also had improved blood-flow recovery from hindlimb ischemia and improved biomechanical properties of the carotid artery. By contrast, the PDE4Dmut had no beneficial effects in T1D. FN signaling through integrin α5 is thus a major contributor to diabetic vascular disease but not through its interaction with PDE4D.
Assuntos
Diabetes Mellitus Tipo 1 , Fibronectinas , Integrina alfa5 , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Células Endoteliais/metabolismo , Fibronectinas/metabolismo , Integrina alfa5/metabolismo , Camundongos , Transdução de SinaisRESUMO
Aortic dissection and rupture are triggered by decreased vascular wall strength and/or increased mechanical loads. We investigated the role of mTOR signaling in aortopathy using a well-described model of angiotensin II-induced dissection, aneurysm, or rupture of the suprarenal abdominal aorta in Apoe-deficient mice. Although not widely appreciated, nonlethal hemorrhagic lesions present as pseudoaneurysms without significant dissection in this model. Angiotensin II-induced aortic tears result in free rupture, contained rupture with subadventitial hematoma (forming pseudoaneurysms), dilatation, or healing, while the media invariably thickens regardless of mural tears. Medial thickening results from smooth muscle cell hypertrophy and extracellular matrix accumulation, including matricellular proteins. Angiotensin II activates mTOR signaling in vascular wall cells, and inhibition of mTOR signaling by rapamycin prevents aortic rupture but promotes dissection. Decreased aortic rupture correlates with decreased inflammation and metalloproteinase expression, whereas extensive dissection correlates with induction of matricellular proteins that modulate adhesion of vascular cells. Thus, mTOR activation in vascular wall cells determines whether aortic tears progress to dissection or rupture. Previous mechanistic studies of aortic aneurysm and dissection by angiotensin II in Apoe-deficient mice should be reinterpreted as clinically relevant to pseudoaneurysms, and mTOR inhibition for aortic disease should be explored with caution.
Assuntos
Falso Aneurisma/prevenção & controle , Aneurisma da Aorta Torácica/prevenção & controle , Ruptura Aórtica/prevenção & controle , Regulação da Expressão Gênica , Inibidores de MTOR/farmacologia , Serina-Treonina Quinases TOR/genética , Falso Aneurisma/genética , Falso Aneurisma/metabolismo , Angiotensina II/toxicidade , Animais , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Ruptura Aórtica/genética , Modelos Animais de Doenças , Progressão da Doença , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , RNA/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/biossínteseRESUMO
The evolving microstructure and mechanical properties that promote homeostasis in the aorta are fundamental to age-specific adaptations and disease progression. We combine ex vivo multiphoton microscopy and biaxial biomechanical phenotyping to quantify and correlate layer-specific microstructural parameters, for the primary extracellular matrix components (fibrillar collagen and elastic lamellae) and cells (endothelial, smooth muscle, and adventitial), with mechanical properties of the mouse aorta from weaning through natural aging up to one year. The aging endothelium was characterized by progressive reductions in cell density and altered cellular orientation. The media similarly showed a progressive decrease in smooth muscle cell density and alignment though with inter-lamellar widening from intermediate to older ages, suggesting cell hypertrophy, matrix accumulation, or both. Despite not changing in tissue thickness, the aging adventitia exhibited a marked thickening and straightening of collagen fiber bundles and reduction in cell density, suggestive of age-related remodeling not growth. Multiple microstructural changes correlated with age-related increases in circumferential and axial material stiffness, among other mechanical metrics. Because of the importance of aging as a risk factor for cardiovascular diseases, understanding the normal progression of structural and functional changes is essential when evaluating superimposed disease-related changes as a function of the age of onset.
Assuntos
Envelhecimento/fisiologia , Aorta , Fenômenos Biomecânicos/fisiologia , Células Endoteliais , Matriz Extracelular/fisiologia , Miócitos de Músculo Liso , Animais , Aorta/citologia , Aorta/crescimento & desenvolvimento , Aorta/ultraestrutura , Senescência Celular/fisiologia , Colágeno/metabolismo , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Fibroblastos/patologia , Fibroblastos/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologiaRESUMO
Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.
Assuntos
Túnica Adventícia , Hipertensão , Túnica Adventícia/patologia , Animais , Aorta/patologia , Aorta Torácica/patologia , Modelos Animais de Doenças , Fibrose , Hipertensão/patologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/patologiaRESUMO
OBJECTIVES: Increased central artery stiffness associates with cardiovascular disease. Among other factors, hypertension and aging are strong contributors to central artery stiffening, yet it has been difficult to separate their effects. Herein, we study isolated and combined effects of hypertension and aging on central artery remodeling in multiple mouse models as a function of sex. METHODS: We biomechanically phenotyped the aorta as a function of two different methods of inducing hypertension [infusion of angiotensin II (AngII) or combining a high salt diet with inhibition of endothelial-derived nitric oxide synthase using L-NAME] in male and female wild-type and fibulin-5 null mice, the latter of which models aspects of aortic aging. RESULTS: Despite increasing blood pressure similarly, saltâ+âL-NAME led to adaptive and maladaptive remodeling in the abdominal and thoracic aorta, respectively, whereas AngII caused luminal dilatation but little remodeling of the wall. Importantly, effects of aging were more dramatic than those resulting from induced hypertension and, consequently, superimposing hypertension on aging led to modest additional changes in luminal radius and wall thickness, though wall stress and stiffness increased mainly because of the elevated pressure. CONCLUSION: Our results suggest that effects of hypertension on aortic remodeling are modest when superimposed on aging in mice, largely independent of sex. These findings are consistent with general observations in humans and in spontaneously hypertensive rats, though separated here for the first time in a rodent model characterized by a severe loss of elastic fiber integrity similar to that found in the aged human aorta.