RESUMEN
Sustained changes in blood flow modulate the size of conduit arteries through structural alterations of the vessel wall that are dependent on the transient accumulation and activation of perivascular macrophages. The leukocytic infiltrate appears to be confined to the adventitia, is responsible for medial remodeling, and resolves once hemodynamic stresses have normalized without obvious intimal changes. We report that inward remodeling of the mouse common carotid artery after ligation of the ipsilateral external carotid artery is dependent on the chemokine receptor CXCR3. Wild-type myeloid cells restored flow-mediated vascular remodeling in CXCR3-deficient recipients, adventitia-infiltrating macrophages of Gr1(low) resident phenotype expressed CXCR3, the perivascular accumulation of macrophages was dependent on CXCR3 signaling, and the CXCR3 ligand IP-10 was sufficient to recruit monocytes to the adventitia. CXCR3 also contributed to selective features of macrophage activation required for extracellular matrix turnover, such as production of the transglutaminase factor XIII A subunit. Human adventitial macrophages displaying a CD14(+)/CD16(+) resident phenotype, but not circulating monocytes, expressed CXCR3, and such cells were more frequent at sites of disturbed flow. Our observations reveal a CXCR3-dependent accumulation and activation of perivascular macrophages as a necessary step in homeostatic arterial remodeling triggered by hemodynamic stress in mice and possibly in humans as well.
Asunto(s)
Homeostasis , Macrófagos/inmunología , Neovascularización Fisiológica , Receptores CXCR3/inmunología , Estrés Fisiológico , Adolescente , Adulto , Anciano , Animales , Arterias/inmunología , Niño , Preescolar , Femenino , Humanos , Macrófagos/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Receptores CXCR3/deficiencia , Receptores CXCR3/metabolismo , Transducción de Señal , Tromboplastina/biosíntesis , Adulto JovenRESUMEN
Vascular remodeling normalizes abnormal hemodynamic stresses through structural changes affecting vessel size and wall thickness. We investigated the role of inflammation in flow-mediated vascular remodeling using a murine model of partial outflow reduction without flow cessation or neointima formation. Common carotid arteries decreased in size after ipsilateral external carotid artery ligation in wild-type mice, but not in myeloid differentiation protein-88 (MyD88)-deficient mice. Inward remodeling was associated with MyD88-dependent and superoxide-initiated cytokine and chemokine production, as well as transient adventitial macrophage accumulation and activation. Macrophage depletion prevented flow-mediated inward vascular remodeling. Expression of MyD88 by intrinsic vascular cells was necessary for cytokine and chemokine production and changes in vessel size, whereas MyD88 expression by bone marrow-derived cells was obligatory for changes in vessel size. We conclude that there are at least two distinct roles for MyD88 in flow-mediated inward remodeling of conduit arteries. Our findings suggest that inflammation is necessary for vascular adaptation to changes in hemodynamic forces.
Asunto(s)
Arteria Carótida Común , Hemodinámica , Inflamación/inmunología , Factor 88 de Diferenciación Mieloide , Superóxidos/inmunología , Animales , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/patología , Arteria Carótida Común/anatomía & histología , Arteria Carótida Común/inmunología , Arteria Carótida Común/patología , Estenosis Carotídea/metabolismo , Estenosis Carotídea/patología , Quimiocinas/inmunología , Citocinas/inmunología , Inflamación/patología , Macrófagos/citología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Flujo Sanguíneo Regional/fisiologíaRESUMEN
BACKGROUND: Graft arteriosclerosis (GA) is an important factor limiting long-term outcomes after organ transplantation. We have used a chimeric humanized mouse system to model this arteriopathy in human vessels, and found that the morphologic and functional changes of experimental GA are interferon (IFN)-gamma dependent. This study evaluated whether 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, described as inhibitors of IFN-gamma production, affect GA in our model. METHODS: C.B.-17 severe combined immunodeficiency-beige mice were transplanted with human artery segments as aortic interposition grafts and inoculated with allogeneic human peripheral blood mononuclear cells (PBMCs) or replication-deficient adenovirus encoding human IFN-gamma. Transplant arteries were analyzed from recipients treated with vehicle vs. atorvastatin or simvastatin at different doses. The effects of statins on T-cell alloresponses to vascular endothelial cells were also investigated in vitro. RESULTS: Graft arteriosclerosis-like arteriopathy induced by PBMCs was reduced by atorvastatin at 30 mg/kg/day or simvastatin at 100 mg/kg/day that correlated with decreased graft-infiltrating CD3+ T cells. Circulating IFN-gamma was also reduced, as were graft IFN-gamma and IFN-gamma-inducible chemokine transcripts and graft human leukocyte antigen-DR expression. Graft arteriosclerosis directly induced by human IFN-gamma in the absence of human PBMCs was also reduced by atorvastatin, but only at the highest dose of 100 mg/kg/day. Finally, atorvastatin decreased the clonal expansion and production of interleukin-2, but not IFN-gamma, by human CD4+ T cells in response to allogeneic endothelial cells in coculture. CONCLUSIONS: Our results suggest that a benefit of statin administration in transplantation may include amelioration of GA primarily by inhibiting alloreactive T-cell accumulation and consequent IFN-gamma production and secondarily through suppression of the arterial response to IFN-gamma.
Asunto(s)
Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Interferón gamma/biosíntesis , Leucocitos Mononucleares/inmunología , Pirroles/uso terapéutico , Simvastatina/uso terapéutico , Linfocitos T/inmunología , Adulto , Animales , Arterias/trasplante , Atorvastatina , Citometría de Flujo , Humanos , Interferón gamma/antagonistas & inhibidores , Transfusión de Linfocitos , Ratones , Ratones SCID , Linfocitos T/efectos de los fármacos , Trasplante Heterólogo/inmunología , Trasplante HomólogoAsunto(s)
Amputación Quirúrgica , Miembros Artificiales , Prótesis de la Rodilla , Diseño de Prótesis , Pie , Humanos , PiernaRESUMEN
BACKGROUND/AIMS: Age-associated changes in endothelial nitric oxide synthase (eNOS) expression have not been definitively linked to the pathophysiology of aortic aneurysms. We examined the role of eNOS in human patients and an age-appropriate mouse model. METHODS: eNOS transcripts and immunodetectable protein were assessed by quantitative PCR and immunohistochemistry in human ascending thoracic aneurysms (n = 29) and referent aortae (n = 31). Carotid aneurysms were induced with CaCl2 in young adult (3 months) and aged (18 months) C57BL/6 and eNOS-knockout (eNOS-KO) mice. RESULTS: eNOS transcripts and protein were reduced in human aneurysms compared with controls, although aortic eNOS expression also decreased with patient age. Aged wild-type mice had significantly larger aneurysm diameter than young adult mice. Aged wild-type mice had reduced eNOS transcripts and protein compared with young adult mice. Aged eNOS-KO mice had smaller aneurysms compared with aged wild-type mice but similar size aneurysms compared with young eNOS-KO and young wild-type mice. CONCLUSION: eNOS expression is reduced in both aged human and aged mouse endothelium and eNOS expression is linked to aneurysm expansion in aged but not young adult mice. These findings support the relevance of age-associated changes in eNOS expression in clinical aneurysmal disease.
Asunto(s)
Envejecimiento/metabolismo , Enfermedades de las Arterias Carótidas/etiología , Aneurisma Intracraneal/etiología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Adulto , Animales , Aorta/enzimología , Aorta/metabolismo , Aneurisma de la Aorta/enzimología , Enfermedades de las Arterias Carótidas/enzimología , Enfermedades de las Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/fisiopatología , Progresión de la Enfermedad , Humanos , Aneurisma Intracraneal/enzimología , Aneurisma Intracraneal/patología , Aneurisma Intracraneal/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/deficiencia , Óxido Nítrico Sintasa de Tipo III/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Progressive medial degeneration and atrophy is thought to be a cause of ascending thoracic aortic aneurysms in the elderly. Extensive apoptosis of vascular smooth muscle cells (VSMCs) has been demonstrated in the media of abdominal aortic aneurysms. We investigated whether medial atrophy from loss of VSMCs occurs in primary ascending thoracic aortic aneurysms. METHODS AND RESULTS: Morphometric analysis of 28 nonaneurysmal ascending thoracic aortas and 29 ascending thoracic aortic aneurysms was performed by directly measuring the thickness of their vascular layers and by indirectly calculating the area of their vascular compartments. The cellular and matrix composition of the media was assessed at the structural, protein, and transcript levels. Despite thinning of the media secondary to vascular dilatation, there was an overall increase in the medial area of aneurysms. VSMC density was preserved, implying cellular hyperplasia as a result of the increased medial mass. There was decreased expression of matrix proteins, despite sustained synthesis of these molecules, which was associated with evidence of increased matrix degradation. The remodeling and expansion of the media was most evident in comparisons between nonaneurysmal aortas versus smaller aneurysms and did not evolve further in larger aneurysms. CONCLUSIONS: The mechanisms for luminal enlargement in thoracic and abdominal aortic aneurysms differ significantly with regard to the survival of VSMCs and atrophy of the media but share common pathophysiology involving degeneration of the matrix. Hyperplastic cellular remodeling of the media in ascending thoracic aortic aneurysms may be an initial adaptive response to minimize increased wall stress resulting from vascular dilatation.
Asunto(s)
Aorta/patología , Aneurisma de la Aorta/patología , Túnica Media/patología , Aorta/enzimología , Aorta/fisiopatología , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/fisiopatología , Apoptosis , Biopsia , Supervivencia Celular , Matriz Extracelular/patología , Humanos , Hiperplasia , Metaloproteinasas de la Matriz/metabolismo , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Túnica Media/enzimología , Túnica Media/fisiopatología , VasodilataciónRESUMEN
Arterial pathology manifests as aneurysmal or obstructive disease depending on changes in lumen size due to vascular remodeling (change in vessel external diameter) and/or intimal expansion. Recent clinical and experimental observations in abdominal aortic aneurysms have led to the emerging dogma that Th2-dominant immune responses result in expansive vascular remodeling and luminal ectasia, whereas Th1 immune responses cause intimal hyperplasia and luminal stenosis. We tested this hypothesis by descriptive analyses of 31 non-aneurysmal and 29 aneurysmal ascending thoracic aortic specimens. Approximately half the aneurysms were distinguished by transmural inflammation. The remaining aneurysms and all the non-aneurysmal aortas had a similar leukocytic infiltrate that spared the inner media. Aneurysm tissue had increased expression of the prototypical Th1 cytokine, interferon (IFN)-gamma, and undetectable Th2 cytokines. Specimens with inner media infiltration displayed robust production of IFN-gamma, induction of the IFN-gamma-inducible chemokines IP-10 and Mig, and recruitment of lymphocytes bearing their cognate receptor CXCR3. Transmural inflammation and IFN-gamma production were associated with increased aortic external diameter, intimal thickening, preserved vascular smooth muscle cell density, and decreased matrix proteins. Th1, but not Th2, immune responses have a positive correlation with both outward vascular remodeling and intimal expansion of ascending thoracic aortic aneurysms.
Asunto(s)
Aneurisma de la Aorta Torácica/patología , Inflamación/patología , Interferón gamma/biosíntesis , Linfocitos T/inmunología , Túnica Íntima/patología , Adolescente , Adulto , Aneurisma de la Aorta Torácica/inmunología , Secuencia de Bases , Antígeno CD56/análisis , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Hiperplasia , Leucocitos/patología , Datos de Secuencia Molecular , Células TH1/inmunologíaRESUMEN
Chemokine receptors preferentially expressed by Th1 cells and their IFN-gamma-inducible ligands predominate in experimental and clinical allograft rejection. Previous chemokine-related transplantation studies have focused on parenchymal and microvascular inflammation which are of importance in acute rejection, but are not necessarily relevant in immune-mediated injury of conduit arteries. We have recently described a model of progressive human T cell-mediated infiltration and injury of allogeneic coronary artery segments using immunodeficient mouse hosts. In the present study, we investigated if recruitment of allogeneic T cells to different vascular compartments correlated with the expression of chemokines and their receptors. Transcripts were quantified by laser capture microdissection/real-time RT-PCR and their distribution was correlated to the corresponding protein expression detected by immunohistochemistry. Infiltrating T cells, confined to the adventitia and intima, expressed CXCR3 and CCR5, but were not recruited into the media despite production by vascular smooth muscle cells of IP-10, Mig, I-TAC, RANTES and MIP-1beta. Chemokine mRNA was detected primarily in vascular cells, although chemokine protein largely localized to infiltrating leukocytes which uniquely expressed their cognate receptors. These data explain the recruitment of IFN-gamma-secreting T cells to the vessel wall, and reinforce the suggestion that the arterial media may be a site of immunological privilege.
Asunto(s)
Rechazo de Injerto/etiología , Trasplante de Corazón/inmunología , Interferón gamma/farmacología , Receptores CCR5/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T/inmunología , Enfermedades Vasculares/etiología , Antineoplásicos/farmacología , Vasos Sanguíneos/inmunología , Vasos Sanguíneos/metabolismo , Células Cultivadas , Quimiocina CCL4 , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Quimiocina CXCL10 , Quimiocina CXCL11 , Quimiocina CXCL9 , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Leucocitos , Proteínas Inflamatorias de Macrófagos/genética , Proteínas Inflamatorias de Macrófagos/metabolismo , Músculo Liso Vascular/inmunología , Músculo Liso Vascular/metabolismo , ARN Mensajero/análisis , Receptores CCR5/inmunología , Receptores CXCR3 , Receptores de Quimiocina/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/metabolismo , Trasplante HomólogoRESUMEN
Vascular remodeling (change in vessel diameter) rather than intimal hyperplasia is the most important predictor of luminal loss in immune-mediated arterial injury, yet little is known about its mechanisms. Here, we show that outward vascular remodeling and intimal thickening, two manifestations of arteriosclerosis with opposing effects on luminal size, result from immune effector mechanisms that are T-cell dependent and interferon (IFN)-gamma mediated. In our in vivo model of human coronary artery injury by allogeneic peripheral blood mononuclear cells, both processes occur concurrently and are characterized by T-cell infiltrates with a predominantly IFN-gamma-producing cytokine profile. Neutralization of IFN-gamma inhibits the arterial and intimal expansion, whereas administration of IFN-gamma enhances these effects. The nonredundant role of IFN-gamma in T-cell-dependent remodeling of human coronary arteries demonstrated here presents a new therapeutic target for preservation of vessel lumen in arteriosclerosis.