RESUMEN
Lower-extremity arterial disease is a major health problem with increasing prevalence, often leading to non-traumatic amputation, disability and mortality. The molecular mechanisms underpinning abnormal vascular wall remodeling are not fully understood. We hypothesized on the existence of a vascular tissue memory that may be transmitted through soluble signaling messengers, transferred from humans to healthy recipient animals, and consequently drive the recapitulation of arterial wall thickening and other vascular pathologies. We examined the effects of the intralesional infiltration for 6 days of arteriosclerotic popliteal artery-derived homogenates (100 µg of protein) into rats' full-thickness wounds granulation tissue. Animals infiltrated with normal saline solution or healthy brachial arterial tissue homogenate obtained from traumatic amputation served as controls. The significant thickening of arteriolar walls was the constant outcome in two independent experiments for animals receiving arteriosclerotic tissue homogenates. This material induced other vascular morphological changes including an endothelial cell phenotypic reprogramming that mirrored the donor's vascular histopathology. The immunohistochemical expression pattern of relevant vascular markers appeared to match between the human tissue and the corresponding recipient rats. These changes occurred within days of administration, and with no cross-species limitation. The identification of these "vascular disease drivers" may pave novel research avenues for atherosclerosis pathobiology.
Asunto(s)
Arteriosclerosis/metabolismo , Tejido de Granulación/metabolismo , Arteria Poplítea/lesiones , Proteínas/administración & dosificación , Lesiones del Sistema Vascular/inducido químicamente , Anciano , Animales , Arteriosclerosis/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Lesiones del Sistema Vascular/patologíaRESUMEN
Cardiovascular diseases are among the main causes of morbimortality in the adult population. Among them, hypertension is a leading cause for stroke, heart disease and kidney failure. Also, as a result of arterial wall weakness, hypertension can lead to the development of dissecting aortic aneurysms, a rare but often fatal condition if not readily treated. In this work, we investigated the role of DBC1 in the regulation of vascular function in an ANGII-induced hypertension mouse model. We found that WT and DBC1 KO mice developed hypertension in response to ANGII infusion. However, DBC1 KO mice showed increased susceptibility to develop aortic dissections. The effect was accompanied by upregulation of vascular remodeling factors, including MMP9 and also VEGF. Consistent with this, we found decreased collagen deposition and elastic fiber fragmentation, suggesting that increased expression of MMPs in DBC1 KO mice weakens the arterial wall, promoting the formation of aortic dissections during treatment with ANGII. Finally, DBC1 KO mice had reduced cell proliferation in the intima-media layer in response to ANGII, paralleled with an impairment to increase wall thickness in response to hypertension. Furthermore, VSMC purified from DBC1 KO mice showed impaired capacity to leave quiescence, confirming the in vivo results. Altogether, our results show for the first time that DBC1 regulates vascular response and function during hypertension and protects against vascular injury. This work also brings novel insights into the molecular mechanisms of the development of aortic dissections.
Asunto(s)
Enfermedades Cardiovasculares/genética , Proteínas de Ciclo Celular/genética , Hipertensión/genética , Proteínas del Tejido Nervioso/genética , Lesiones del Sistema Vascular/genética , Angiotensina II/efectos adversos , Animales , Enfermedades Cardiovasculares/patología , Proliferación Celular/genética , Modelos Animales de Enfermedad , Humanos , Hipertensión/inducido químicamente , Hipertensión/patología , Metaloproteinasa 9 de la Matriz/genética , Ratones , Ratones Noqueados , Factor A de Crecimiento Endotelial Vascular/genética , Lesiones del Sistema Vascular/patologíaRESUMEN
Excessive consumption of carbohydrate and fat increases the risk of cardiovascular disease. We sought to determine the potential ultrastructural alterations in large blood vessels induced by a high fat and fructose diet (HFD) in a rat model of prediabetes. Rats were either fed with HFD (model group) or a standard laboratory chow (control group) for 15 weeks before being sacrificed. The harvested thoracic aorta tissues were examined using transmission electron microscopy (TEM), and blood samples were assayed for biomarkers of pre-diabetes.TEM images showed that HFD induced profound pathological changes to the aortic wall layers, tunica intima and tunica media ultrastructures in the pre-diabetic rats as shown by apoptotic endothelial cells with pyknotic nuclei, damaged basal lamina, deteriorated smooth muscle cells that have irregular plasma membranes, shrunken nucleus with clumped nuclear chromatin, damaged mitochondria and few cytoplasmic lipid droplets and vacuoles. In addition, HFD significantly (p<0.05) decreased adiponectin and increased biomarkers of lipidemia, glycaemia, inflammation, oxidative stress, vascular injury such as soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion protein 1 (sVCAM-1), endothelin-1 (ET-1), and coagulation and thrombosis such as Von Willebrand factor (vWF), and plasminogen activator inhibitor-1 (PAI-1), compared to normal levels of these parameters in the control group. Thus, we demonstrated that feeding rats with a HFDisable to develop a pre-diabetic animal model that is useful to study the aortic ultrastructural alterations.
El consumo excesivo de carbohidratos y grasas aumenta el riesgo de enfermedades cardiovasculares. Intentamos determinar las posibles alteraciones ultraestructurales en los grandes vasos sanguíneos, inducidas por una dieta alta en grasas y fructosa (HFD) en un modelo de rata de prediabetes. Las ratas se alimentaron con HFD (grupo modelo) o una comida de laboratorio estándar (grupo de control) durante 15 semanas antes de ser sacrificadas. Los tejidos de la aorta torácica recolectados se examinaron mediante microscopía electrónica de transmisión (TEM) y las muestras de sangre se analizaron para detectar biomarcadores de prediabetes. Las imágenes TEM mostraron que HFD indujo cambios patológicos profundos en las capas de la pared aórtica, túnica íntima y túnica media en la ratas pre-diabéticas como lo muestran las células endoteliales apoptóticas con núcleos picnóticos, lámina basal dañada, células musculares lisas deterioradas que tienen membranas plasmáticas irregulares, núcleo encogido con cromatina nuclear aglomerada, mitocondrias dañadas y pocas gotitas lipídicas citoplásmicas y vacuolas. Además, HFD presentó disminución significativa de adiponectina (p <0,05), y aumento de biomarcadores de lipidemia, glucemia, inflamación, estrés oxidativo, lesión vascular como la molécula de adhesión intercelular soluble 1 (sICAM-1), proteína de adhesión de células vasculares soluble 1 (sVCAM-1), endotelina 1 (ET-1), y la coagulación y la trombosis, como el factor de Von Willebrand (vWF), y el inhibidor del activador del plasminógeno-1 (PAI -1), en comparación con los niveles normales de estos parámetros en el grupo de control. Por tanto, la alimentación de ratas con HFD es capaz de desarrollar un modelo animal prediabético que es útil para estudiar las alteraciones ultraestructurales aórticas.
Asunto(s)
Animales , Aorta Torácica/patología , Aorta Torácica/ultraestructura , Estado Prediabético/patología , Aorta/patología , Aorta/ultraestructura , Estado Prediabético/metabolismo , Grasas de la Dieta/efectos adversos , Ratas Sprague-Dawley , Microscopía Electrónica de Transmisión , Modelos Animales de Enfermedad , Lesiones del Sistema Vascular/etiología , Lesiones del Sistema Vascular/patología , FructosaRESUMEN
OBJECTIVE: Temporary intravascular shunts (TIVSs) are commonly used as a damagecontrol procedure in trauma settings. Currently, there is scarce literature in the civilian field, and what there is is limited to large trauma centers with multiple resources. Therefore, we aimed to describe TIVS usage, and the outcomes of that usage, at Puerto Rico Trauma Hospital. MATERIALS AND METHODS: This is a case series conducted from 2009 to 2013 with 32 patients who suffered vascular trauma, of which 13 needed TIVSs. Data related to age, trauma mechanism, injured vessel, type of shunt, Glasgow Coma Scale, vital signs, and mortality were collected. The analysis was carried out using descriptive statistics. This protocol was approved by the IRB of the Medical Sciences Campus. RESULTS: The most frequent mechanism of injury was a gunshot (11/13; 84.6%). The most commonly injured vessel was the superficial femoral artery. Indwelling time ranged from 6 to 96 hours. Only 2 of the 13 (15.4%) patients with shunts reported thrombosis. Furthermore, we performed 4 (30.7% of the patients) prophylactic fasciotomies and 4 (30.7% of the patients) amputations; 4 of the 13 (30.7%) patients died from unrelated causes. CONCLUSION: Our results are consistent with those in the literature, which supports our contention that a TIVS can be an effective component of damage-control vascular surgery and can, in both military and civilian settings, aid in extremity amputation prevention. Furthermore, it has been established that a TIVS can be fashioned from any available hollow tube. However, further research is needed to evaluate the safety of an improvised catheter of this nature.
Asunto(s)
Amputación Quirúrgica/estadística & datos numéricos , Procedimientos Quirúrgicos Vasculares/métodos , Lesiones del Sistema Vascular/cirugía , Heridas por Arma de Fuego/cirugía , Adolescente , Adulto , Fasciotomía/estadística & datos numéricos , Femenino , Escala de Coma de Glasgow , Humanos , Masculino , Puerto Rico , Factores de Tiempo , Lesiones del Sistema Vascular/mortalidad , Lesiones del Sistema Vascular/patología , Heridas por Arma de Fuego/epidemiología , Adulto JovenRESUMEN
Resumo A hiperplasia angiolinfoide com eosinofilia (HALE) é considerada uma lesão vascular benigna rara que acomete, principalmente, o tecido cutâneo e subcutâneo da região de cabeça e pescoço, mas incomum na cavidade oral. Sua etiopatogenia permanece indefinida, sendo descrita como proliferação vascular reacional, malformação vascular ou neoplasia. Tem como principal diagnóstico diferencial a doença de Kimura. Este trabalho relata um caso de um paciente do sexo masculino, de 50 anos, que exibia aumento de volume nodular na mucosa do lábio superior, com 3 cm de dimensão e 7 anos de evolução. Após a biópsia excisional, o exame histopatológico mostrou lesão bem encapsulada multilobulada com proliferação de capilares sanguíneos com células endoteliais de aspecto epitelioide, infiltrado inflamatório difuso com linfócitos, plasmócitos, inúmeros eosinófilos e presença de folículos linfoides. A análise imuno-histoquímica revelou positividade para CD34 e Ki-67, o que, juntamente com o exame morfológico, direcionou o diagnóstico para HALE.
Abstract Angiolymphoid Hyperplasia with eosinophilia (ALHE) is considered a rare, benign vascular lesion that mainly affects the skin and subcutaneous tissues of the head and neck, but is uncommon in the oral cavity. Its etiology remains unclear and it has been described as a reactive vascular proliferation, vascular malformation or neoplasm. Kimura's disease is the primary entity to consider in differential diagnosis. Here we report on a rare case of ALHE involving the upper lip of a 50-year-old male patient that had a nodular swelling with approximately 3 cm, 7 years after initial onset. An excisional biopsy was performed and histopathologic examination revealed a well-encapsulated, multi-lobed lesion with proliferation of blood capillaries, displaying endothelial cells of epithelioid appearance, diffuse inflammatory infiltrate with lymphocytes, plasma cells, numerous eosinophils, and presence of lymphoid follicles. Immunohistochemical tests were positive for the markers CD34 and Ki-67 that, in combination with the results of morphological examination, were suggestive of a diagnosis of ALHE.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Hemangioma/irrigación sanguínea , Mucosa Bucal/lesiones , Lesiones del Sistema Vascular/patologíaRESUMEN
OBJECTIVE: To evaluate the behavior of castor oil-derived polyurethane as a hemostatic agent and tissue response after abdominal aortic injury and to compare it with 2-octyl-cyanoacrylate. METHODS: Twenty-four Guinea Pigs were randomly divided into three groups of eight animals (I, II, and III). The infrarenal abdominal aorta was dissected, clamped proximally and distally to the vascular puncture site. In group I (control), hemostasis was achieved with digital pressure; in group II (polyurethane) castor oil-derived polyurethane was applied, and in group III (cyanoacrylate), 2-octyl-cyanoacrylate was used. Group II was subdivided into IIA and IIB according to the time of preparation of the hemostatic agent. RESULTS: Mean blood loss in groups IIA, IIB and III was 0.002 grams (g), 0.008 g, and 0.170 g, with standard deviation of 0.005 g, 0.005 g, and 0.424 g, respectively (P=0.069). The drying time for cyanoacrylate averaged 81.5 seconds (s) (standard deviation: 51.5 seconds) and 126.1 s (standard deviation: 23.0 s) for polyurethane B (P=0.046). However, there was a trend (P=0.069) for cyanoacrylate to dry more slowly than polyurethane A (mean: 40.5 s; SD: 8.6 s). Furthermore, polyurethane A had a shorter drying time than polyurethane B (P=0.003), mean IIA of 40.5 s (standard deviation: 8.6 s). In group III, 100% of the animals had mild/severe fibrosis, while in group II only 12.5% showed this degree of fibrosis (P=0.001). CONCLUSION: Polyurethane derived from castor oil showed similar hemostatic behavior to octyl-2-cyanoacrylate. There was less perivascular tissue response with polyurethane when compared with cyanoacrylate.
Asunto(s)
Cianoacrilatos/farmacología , Hemostasis Quirúrgica/métodos , Hemostáticos/farmacología , Poliuretanos/farmacología , Adhesivos Tisulares/farmacología , Lesiones del Sistema Vascular/cirugía , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/patología , Aorta Abdominal/cirugía , Aceite de Ricino/química , Cianoacrilatos/uso terapéutico , Modelos Animales de Enfermedad , Fibrosis , Cobayas , Hemostáticos/uso terapéutico , Masculino , Ensayo de Materiales , Poliuretanos/uso terapéutico , Distribución Aleatoria , Reproducibilidad de los Resultados , Factores de Tiempo , Adhesivos Tisulares/uso terapéutico , Resultado del Tratamiento , Lesiones del Sistema Vascular/patologíaRESUMEN
BACKGROUND: Intimal hyperplasia (restenosis) is an exaggerated healing response leading to failure of half of vascular interventions. Increasing evidence suggests that circulating progenitor cells contribute to intimal pathology, and clinical studies have demonstrated a correlation between progenitor cells and the incidence of restenosis after cardiovascular interventions. The aims of this study were to characterize the temporal response of CD34+ progenitors following vascular injury in an ovine model and to evaluate an affinity pheresis approach to attenuate this response. METHODS: An ovine model underwent either operative vascular injury or a nonvascular surgery (n = 3 per group). Blood was examined perioperatively over 2 weeks by flow cytometry. Next, an affinity pheresis approach to mediate systemic depletion of CD34 progenitors was designed. Custom agarose pheresis matrix with antibody affinity toward CD34 or an isotype control was evaluated in vitro. Next, following vascular injury, sheep underwent perioperative whole blood volume pheresis toward either the progenitor cell marker CD34 (n = 3) or an isotype control (n = 4) for 14 days. Animals were monitored by physical exam as well as complete blood counts. Cells recovered by pheresis were eluted and examined by flow cytometry. RESULTS: Flow cytometry revealed a focal surge of circulating CD34 cells after vascular injury but not among surgical controls (P = .05). Toward the goal of an approach to attenuate the surge of CD34 progenitors, an evaluation of high-flow affinity matrix revealed efficacy in removal of progenitors from ovine blood in vitro. Next, a separate group of animals undergoing affinity pheresis after vascular injury was evaluated to mediate systemic depletion of CD34+ cells. Again, a surge of CD34+ cells was observed among isotype pheresis animals following vascular intervention but was attenuated over 20-fold by a CD34 pheresis approach (P = .029). Furthermore, an average of 77 million CD34-positive cells were eluted from the CD34 pheresis matrix. Despite multiple sessions of pheresis, complete blood counts remained essentially unchanged over 2 weeks. CONCLUSIONS: Despite evidence suggesting a role for CD34+ circulating progenitor cells in restenotic pathology, the temporal pattern of CD34 progenitors after vascular injury has not been previously defined. We have demonstrated a surge among circulating CD34+ cells that appears confined to procedures involving vascular injury and that this event seems to occur early after vascular injury. We further conclude that CD34 affinity pheresis attenuates the surge. This approach for direct depletion of progenitors may have important implications for the study of progenitors in vascular restenosis.
Asunto(s)
Antígenos CD34/inmunología , Eliminación de Componentes Sanguíneos/métodos , Endotelio Vascular/inmunología , Células Madre/inmunología , Lesiones del Sistema Vascular/terapia , Animales , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Femenino , Citometría de Flujo , Ovinos , Células Madre/citología , Resultado del Tratamiento , Lesiones del Sistema Vascular/patologíaRESUMEN
Drug-eluting stents have proven to be effective in reducing the risk of late restenosis. In order to achieve a controlled and prolonged release of the antiproliferative agent, current drug-eluting stents utilise various biodegradable as well as non-erodible polymeric blends to coat the stent surface and to serve as drug carriers. The utilisation of polymeric compounds in current drug-eluting stents may eventually limit their performance as well as their clinical applicability due to the potential induction of undesirable local reactions. The development of alternative, polymer-free drug carriers has the potential to overcome some of the limitations of current drug-eluting stent formulations. Moreover, improvements in drug carriers may also result in an expansion of the technological possibilities for other intravascular drug delivery systems, such as metal-free or even implant-free solutions. This article describes the structure and the preclinical validation profile of a novel phospholipid encapsulated sirolimus nanocarrier, used as a coating in two formulations: a coronary stent-plus-balloon system and a stand-alone balloon catheter. The nanoparticles provided a stable, even and homogenous coating to the devices in both formulations. Dose-finding studies allowed the most appropriate identification of the best nanoparticle structure associated with an extremely efficient transfer of drug to all layers of the vessel wall, achieving high tissue concentrations that persisted days after the application, with low systemic drug leaks.
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Angioplastia de Balón/instrumentación , Fármacos Cardiovasculares/administración & dosificación , Catéteres , Materiales Biocompatibles Revestidos , Portadores de Fármacos , Stents Liberadores de Fármacos , Nanopartículas , Fosfolípidos/química , Sirolimus/administración & dosificación , Animales , Fármacos Cardiovasculares/sangre , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacocinética , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Arteria Femoral/lesiones , Arteria Femoral/metabolismo , Arteria Ilíaca/lesiones , Arteria Ilíaca/metabolismo , Cinética , Masculino , Conejos , Sirolimus/sangre , Sirolimus/química , Sirolimus/farmacocinética , Porcinos , Distribución Tisular , Lesiones del Sistema Vascular/sangre , Lesiones del Sistema Vascular/patología , Lesiones del Sistema Vascular/terapiaRESUMEN
PURPOSE: To assess the intrarenal arteries injuries after cranial pole nephrectomy in a pig model to compare these findings with those in humans. MATERIALS AND METHODS: Polyester resin was injected through the ureter and the renal artery to make three-dimensional casts of 61 pig kidneys. The cranial pole of the kidneys was sectioned at four different sites before the solidification of the resin, and the casts were examined for arterial damage. RESULTS: Section performed through the hilus (15 kidneys): The cranial division of the renal artery was sectioned in two (13.33%) cases, the ventral branch of the cranial division of the renal artery was sectioned in 13 (86.7%) cases, and the dorsal branch of the cranial division of the renal artery was sectioned in 11 (73.34%) cases. Section at 0.5 cm cranial to the hilus (16 kidneys): The cranial division of the renal artery was sectioned in 1 (6.25%) case, the ventral branch of the cranial division of the renal artery was sectioned in 14 (87.5%) cases, and the dorsal branch of the cranial division of the renal artery was sectioned in 13 (81.25%) cases. Section at 1.0 cm cranial to the hilus (15 kidneys): The ventral branch of the cranial division of the renal artery was sectioned in five (33.33%) cases, and the dorsal branch of the cranial division of the renal artery was injured in five (33.33%) cases. Section at 1.5 cm cranial to the hilus (15 kidneys): No lesions were found in the main arteries, only in the interlobular branches. CONCLUSIONS: As previously demonstrated in humans, sections at 1.0 cm or more cranially to the hilus in pigs also showed a significant decrease in damage to the major intrarenal arteries. Therefore, as regards arterial damage, the pig kidney is a useful model for partial nephrectomy in the cranial (upper) pole.