RESUMEN
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.
Asunto(s)
Aneurisma Falso/prevención & control , Aneurisma de la Aorta Torácica/prevención & control , Rotura de la Aorta/prevención & control , Regulación de la Expresión Génica , Inhibidores mTOR/farmacología , Serina-Treonina Quinasas TOR/genética , Aneurisma Falso/genética , Aneurisma Falso/metabolismo , Angiotensina II/toxicidad , Animales , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/patología , Rotura de la Aorta/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , ARN/genética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/biosíntesisRESUMEN
PURPOSE: The causes and pathogenetic mechanisms underlying abdominal aortic aneurysms (AAAs) and pseudoaneurysms are not fully understood. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease AAA and pseudoaneurysm formation in mouse and rat models. METHODS: Human AAA samples were examined in conjunction with an adventitial calcium chloride (CaCl2) application mouse model and an aortic patch angioplasty rat model. Single-dose PD-1 antibody (4 mg/kg) or BMS-1 (PD-1 inhibitor-1) (1 mg/kg) was administered by intraperitoneal (IP) or intraluminal injection. In the intramural injection group, PD-1 antibody was injected after CaCl2 incubation. The rats were divided into three groups: (1) the control group was only decellularized without other special treatment, (2) the PD-1 antibody-coated patch group, and (3) the BMS-1 coated patch group. Patches implanted in the rat abdominal aorta were harvested on day 14 after implantation and analyzed. RESULTS: Immunohistochemical analysis showed PD-1-positive cells, PD-1 and CD3, PD-1 and CD68, and PD-1 and α-actin co-expressed in the human AAA samples. Intraperitoneal (IP) injection or intraluminal injection of PD-1antibody/BMS-1 significantly inhibited AAA progression. PD-1 antibody and BMS-1 were each successfully conjugated to decellularized rat thoracic artery patches, respectively, by hyaluronic acid. Patches coated with either humanized PD-1 antibody or BMS-1 can also inhibit pseudoaneurysm progression and inflammatory cell infiltration. CONCLUSION: PD-1 pathway inhibition may be a promising therapeutic strategy for inhibiting AAA and pseudoaneurysm progression.
Asunto(s)
Aneurisma Falso/tratamiento farmacológico , Aneurisma Falso/metabolismo , Aneurisma de la Aorta Abdominal/tratamiento farmacológico , Aneurisma de la Aorta Abdominal/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Aneurisma Falso/patología , Angioplastia/métodos , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Aneurisma de la Aorta Abdominal/patología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Cloruro de Calcio/toxicidad , Materiales Biocompatibles Revestidos/farmacología , Materiales Biocompatibles Revestidos/uso terapéutico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inyecciones Intraperitoneales , Linfocitos/inmunología , Macrófagos/inmunología , Masculino , Ratones , Receptor de Muerte Celular Programada 1/inmunología , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: Aneurysms are generally the result of dilation of all 3 layers of the vessel wall, and pseudoaneurysms are the result of localized extravasation of blood that is contained by surrounding tissue. Since there is still no recommended protocol to decrease aneurysm formation and progression, we hypothesised that intramural delivery of TGF ß1 hydrogel can decrease aneurysm and pseudoaneurysm formation and progression. MATERIALS: Male C57BL/6 J mice (12-14 wk), SD rats (200 g) and pig abdominal aortas were used, and hydrogels were fabricated by the interaction of sodium alginate (SA), hyaluronic acid (HA) and CaCO3. METHODS: A CaCl2 adventitial incubation model in mice and a decellularized human great saphenous vein patch angioplasty model in rats were used. TGF ß1 hydrogel was intramurally delivered after CaCl2 incubation in mice; at day 7, the abdomen in some mice was reopened, and TGF ß1 hydrogel was injected intramurally into the aorta. In rats, TGF ß1 hydrogel was delivered intramurally after patch angioplasty completion. Tissues were harvested at day 14 and analysed by histology and immunohistochemistry staining. The pig aorta was also intramurally injected with hydrogel. RESULTS: In mice, rhodamine hydrogel was still found between the medium and adventitia at day 14. In the mouse aneurysm model, there was a thicker wall and smaller amount of elastin breaks in the TGF ß1 hydrogel-delivered groups both at day 0 and day 7 after CaCl2 incubation, and there were larger numbers of p-smad2- and TAK1-positive cells in the TGF ß1 hydrogel-injected groups. In the rat decellularized human saphenous vein patch pseudoaneurysm model, there was a higher incidence of pseudoaneurysm formation when the patch was decellularized using 3% SDS, and delivery of TGF ß1 hydrogel could effectively decrease the formation of pseudoaneurysm formation and increase p-smad2 and TAK1 expression. In pig aortas, hydrogels can be delivered between the medium and adventitia easily and successfully. CONCLUSIONS: Intramural delivery of TGF ß1 hydrogel can effectively decease aneurysm and pseudoaneurysm formation and progression in both mice and rats, and pig aortas can also be successfully intramurally injected with hydrogel. This technique may be a promising drug delivery method and therapeutic choice to decrease aneurysm and pseudoaneurysm formation and progression in the clinic.
Asunto(s)
Aneurisma Falso/prevención & control , Aorta Abdominal/efectos de los fármacos , Aneurisma de la Aorta Abdominal/prevención & control , Portadores de Fármacos , Factor de Crecimiento Transformador beta1/administración & dosificación , Aneurisma Falso/metabolismo , Aneurisma Falso/patología , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Preparaciones de Acción Retardada , Dilatación Patológica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Composición de Medicamentos , Hidrogeles , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Ratones Endogámicos C57BL , Fosforilación , Ratas Sprague-Dawley , Proteína Smad2/metabolismo , Sus scrofaRESUMEN
OBJECTIVE: Pseudoaneurysms remain a significant complication after vascular procedures. We hypothesized that TGF-ß (transforming growth factor-ß) signaling plays a mechanistic role in the development of pseudoaneurysms. APPROACH AND RESULTS: Rat aortic pericardial patch angioplasty was associated with a high incidence (88%) of pseudoaneurysms at 30 days, with increased smad2 phosphorylation in small pseudoaneurysms but not in large pseudoaneurysms; TGF-ß1 receptors were increased in small pseudoaneurysms and preserved in large pseudoaneurysms. Delivery of TGF-ß1 via nanoparticles covalently bonded to the patch stimulated smad2 phosphorylation both in vitro and in vivo and significantly decreased pseudoaneurysm formation (6.7%). Inhibition of TGF-ß1 signaling with SB431542 decreased smad2 phosphorylation both in vitro and in vivo and significantly induced pseudoaneurysm formation by day 7 (66.7%). CONCLUSIONS: Normal healing after aortic patch angioplasty is associated with increased TGF-ß1 signaling, and recruitment of smad2 signaling may limit pseudoaneurysm formation; loss of TGF-ß1 signaling is associated with the formation of large pseudoaneurysms. Enhancement of TGF-ß1 signaling may be a potential mechanism to limit pseudoaneurysm formation after vascular intervention.
Asunto(s)
Aneurisma Falso/prevención & control , Angioplastia/instrumentación , Aorta/cirugía , Aneurisma de la Aorta/prevención & control , Materiales Biocompatibles Revestidos , Pericardio/trasplante , Factor de Crecimiento Transformador beta1/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , Aneurisma Falso/etiología , Aneurisma Falso/metabolismo , Aneurisma Falso/patología , Angioplastia/efectos adversos , Animales , Aorta/metabolismo , Aorta/patología , Aneurisma de la Aorta/etiología , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/patología , Células Cultivadas , Masculino , Ratones , Nanopartículas , Fosforilación , Diseño de Prótesis , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Proteína Smad2/metabolismo , Factores de TiempoRESUMEN
We present a case of a 58-year-old female with a rare vascular tumor of intermediate malignancy. The initial manifestation was a pseudoaneurysm caused by the rupture of the right pulmonary artery after tumor invasion. The diagnosis of epithelioid hemangioendothelioma was confirmed by the morphologic and immunocytochemical features after surgery. The patient recovered smoothly and there has been no evidence of local recurrence or metastasis during the 2 years of follow-up.
Asunto(s)
Aneurisma Falso/etiología , Hemangioendotelioma Epitelioide/complicaciones , Neoplasias Pulmonares/complicaciones , Arteria Pulmonar , Aneurisma Falso/diagnóstico , Aneurisma Falso/metabolismo , Aneurisma Falso/cirugía , Biomarcadores de Tumor/análisis , Biopsia , Femenino , Hemangioendotelioma Epitelioide/química , Hemangioendotelioma Epitelioide/patología , Hemangioendotelioma Epitelioide/cirugía , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Persona de Mediana Edad , Invasividad Neoplásica , Arteria Pulmonar/química , Arteria Pulmonar/patología , Arteria Pulmonar/cirugía , Toracotomía , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: Impairment of transforming growth factor (TGF)-beta1 signaling accelerates atherosclerosis in experimental mice. However, it is uncertain whether increased TGF-beta1 expression would retard atherosclerosis. The role of TGF-beta1 in aneurysm formation is also controversial. We tested whether overexpression of active TGF-beta1 in hyperlipidemic mice affects atherogenesis and aortic dilation. METHODS AND RESULTS: We generated apolipoprotein E-null mice with transgenes that allow regulated overexpression of active TGF-beta1 in their hearts. Compared to littermate controls, these mice had elevated cardiac and plasma TGF-beta1, less aortic root atherosclerosis (P< or =0.002), fewer lesions in the thoracic and abdominal aortae (P< or =0.01), less aortic root dilation (P<0.001), and fewer pseudoaneurysms (P=0.02). Mechanistic studies revealed no effect of TGF-beta1 overexpression on plasma lipids or cytokines, or on peripheral lymphoid organ cells. However, aortae of TGF-beta1-overexpressing mice had fewer T-lymphocytes, more collagen, less lipid, lower expression of inflammatory cytokines and matrix metalloproteinase-13, and higher expression of tissue inhibitor of metalloproteinase-2. CONCLUSIONS: When overexpressed in the heart and plasma, TGF-beta1 is an antiatherogenic, vasculoprotective cytokine that limits atherosclerosis and prevents aortic dilation. These actions are associated with significant changes in cellularity, collagen and lipid accumulation, and gene expression in the artery wall.
Asunto(s)
Aneurisma Falso/prevención & control , Aneurisma de la Aorta/prevención & control , Apolipoproteínas E/deficiencia , Aterosclerosis/prevención & control , Hiperlipidemias/metabolismo , Miocardio/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Aneurisma Falso/genética , Aneurisma Falso/metabolismo , Aneurisma Falso/patología , Animales , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/patología , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Colágeno/metabolismo , Dilatación Patológica , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Hiperlipidemias/complicaciones , Hiperlipidemias/genética , Hiperlipidemias/patología , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Transducción de Señal , Linfocitos T/inmunología , Factores de Tiempo , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
The mechanism of pseudoaneurysm formation caused by prolonged sepsis is thought to be related to the vascular endothelium being directly invaded and broken by bacteria. Moreover, matrix metalloproteinases (MMPs) which are up-regulated by chronic inflammation have been reported to be implicated in the pathogenesis of aneurysm development through increased proteolysis of extracellular matrix proteins. An effective treatment for infected pseudoaneurysm remains unsettled. Surgery is generally performed, however, because the patients in most of these cases are in very poor physical condition, the operation is associated with high morbidity and mortality. A more successful alternative is endovascular treatment. Recent reports indicate low morbidity and mortality rates with this treatment. If the patient in this case had been in better condition, we could have selected endovascular stent-grafting for her treatment.
Asunto(s)
Aneurisma Falso/microbiología , Aorta Abdominal , Sepsis/complicaciones , Infecciones Estafilocócicas/complicaciones , Anciano , Aneurisma Falso/diagnóstico por imagen , Aneurisma Falso/metabolismo , Resultado Fatal , Femenino , Humanos , Metaloproteinasas de la Matriz/metabolismo , Resistencia a la Meticilina , Sepsis/metabolismo , Infecciones Estafilocócicas/metabolismo , Tomografía Computarizada por Rayos XRESUMEN
The distribution of proteoglycans in 21 temporal and two ulnar artery pseudoaneurysms was studied immunohistochemically. A history of trauma was elicited in six cases, and 16 of the lesions were pulsatile. The clinical diagnosis was aneurysm or cyst in 18 patients, possible arteritis in two patients, tumor in one patient, and unknown in the remaining patient. Histologically, there was a prominent myxoid neointimal response in the walls of each interrupted artery. The remnant arterial segment was often inconspicuous. Prominent smooth muscle cell proliferation and granulation tissue response with inflammation led to misdiagnosis of tumor or vasculitis, respectively, in 11 cases. Immunohistochemical staining for proteoglycans demonstrated abundant, diffuse versican in interrupted wall segments. Biglycan was confined to collagenized and vascularized areas. In some portions of medial disruption, in which angiogenesis was prominent, decorin was expressed within endothelial cells of neocapillaries. These findings demonstrate that superficial pseudoaneurysms may be mistaken clinically and pathologically for unrelated entities. The immunohistochemical studies confirm that versican is upregulated in areas of tensile stress. In addition, the presence of endothelial expression of decorin supports the concept of decorin's involvement in angiogenesis.
Asunto(s)
Aneurisma Falso/patología , Matriz Extracelular/metabolismo , Proteoglicanos/metabolismo , Arterias Temporales/patología , Adolescente , Adulto , Anciano , Aneurisma Falso/etiología , Aneurisma Falso/metabolismo , Biglicano , Biomarcadores/análisis , Niño , Proteoglicanos Tipo Condroitín Sulfato/análisis , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Decorina , Matriz Extracelular/química , Proteínas de la Matriz Extracelular , Femenino , Humanos , Técnicas para Inmunoenzimas , Lectinas Tipo C , Masculino , Persona de Mediana Edad , Proteoglicanos/análisis , Arterias Temporales/metabolismo , Arteria Cubital/metabolismo , Arteria Cubital/patología , VersicanosRESUMEN
UNLABELLED: OBJECTIVES; The goal of this study was to assess the safety and efficacy of femoral artery pseudoaneurysm (FAP) closure by collagen injection. BACKGROUND; The FAP is an infrequent but troublesome complication after percutaneous transfemoral catheter procedures. If ultrasound-guided compression repair (UGCR) fails, vascular surgery is indicated. We have developed a less invasive method to close FAPs percutaneously by injecting collagen and, thus, inducing clotting within the aneurysm. METHODS: Via a 9F needle or 11F sheath, a biodegradable adhesive bovine collagen is injected percutaneously into the FAP, guided by angiography from the contralateral site. RESULTS: From 1993 to 2000, compression and UGCR had failed to obliterate 110 FAPs. These patients have been treated by collagen injection. Mean age of the patients was 65.6 +/- 10.2 years (range: 32 to 85 years), and 50% were women. Immediate closure of the FAP was achieved in 107/110 patients (97.3%) without any complication or adverse effect. In one patient the collagen could not be applied due to unfavorable anatomy. One patient needed a second session of collagen injection. In one patient too much collagen was inserted, which resulted in external compression of the artery, and surgical intervention was required. The overall success rate was 108/110 (98%, 95% confidence interval: 93.5% to 99.8%). Among the patients with successful procedures, there were no recurrences during six months follow-up. CONCLUSIONS: The percutaneous treatment of iatrogenic FAP, by injection with collagen, is an effective and safe strategy. This method provides an excellent therapeutic alternative to the traditional surgical management.
Asunto(s)
Aneurisma Falso/tratamiento farmacológico , Aneurisma Falso/metabolismo , Colágeno/uso terapéutico , Arteria Femoral/química , Arteria Femoral/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Cateterismo Cardíaco , Femenino , Estudios de Seguimiento , Humanos , Enfermedad Iatrogénica , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Países Bajos , Resultado del TratamientoRESUMEN
We describe a vascular lesion that develops secondary to trauma (pseudotraumatic aneurysm) and study its relation to epithelioid hemangioma (EH)/angiolymphoid hyperplasia with eosinophilia (ALHE). Four lesions are described, all with a distinct history of trauma to the site from which they arose. They presented with masses in the subcutaneous tissue of the head. They were studied by immunohistochemical methods to identify their component cells. The lesions all demonstrated marked thickening of the wall of small and medium-sized arteries, with capillary vascular proliferations. One lesion demonstrated increased eosinophils. Myxoid changes were noted in all lesions. We hypothesize that these lesions may represent an early form of EH/ALHE.
Asunto(s)
Aneurisma Falso/diagnóstico , Hiperplasia Angiolinfoide con Eosinofilia/diagnóstico , Heridas y Lesiones/complicaciones , Adolescente , Adulto , Aneurisma Falso/etiología , Aneurisma Falso/metabolismo , Aneurisma Falso/patología , Hiperplasia Angiolinfoide con Eosinofilia/metabolismo , Hiperplasia Angiolinfoide con Eosinofilia/patología , Antígenos CD34/metabolismo , Factor VIII/metabolismo , Femenino , Humanos , Inmunohistoquímica , MasculinoRESUMEN
Aneurysms are morphologically classified as true or false based on the nature of their walls. True aneurysms are composed of all or parts of layers of the vessel. False aneurysms are the result of rupture and their walls have only fibrous tissues. The orifice of false aneurysms is narrow relative to the aneurysmal diameter and thus they are grossly or angiographically referred to as punched-out lesions. Hence false aneurysms present with punched-out lesions, but in reverse, are all of punched-out lesions false aneurysms? We experienced some cases of punched-out lesions which histologically contained traces of elastin, and the purpose of this report was to histologically investigate grossly punched-out lesions. We examined 671 elderly autopsy cases, and a total of 21 grossly punched-out lesions in the aorto-iliac region were selected. They were histologically classified as false, "pseudo-false", or "disguised" aneurysm. False aneurysms were found in 3 patients (0.45%), and were histologically mycotic. A total of 5 "pseudo-false" aneurysms were found in 3 patients (0.45%). They histologically contained traces of elastin, and thus they were categorised in true aneurysms. A total of 13 "disguised" aneurysms were found in 6 patients (0.89%). They were true fusiform aneurysms with an eccentric thrombus, on which a fibrin-cap formed a narrow orifice. Partial sections are insufficient for diagnosis; cross-sections are necessary. To the best of our knowledge, there have been no reports of "pseudo-false" or "disguised" aneurysms in the aorto-iliac region.