RESUMO
Matrix metalloproteinase-1 (MMP-1) is a collagenase that is highly active in extracellular matrix and vascular remodeling, angiogenesis, and tumor progression. Vascular endothelial growth factor receptor-2 (VEGFR2), the main receptor for VEGF-A, is expressed on endothelial cells and promotes cell survival, proliferation, and other functions. Although MMP-1 and VEGFR2 co-exist in many normal and pathophysiological conditions, the effect of MMP-1 on cellular VEGFR2 that can promote the above processes is unknown. In this study we test the hypothesis that stimulation of endothelial cells with MMP-1 increases their levels of VEGFR2. The increased VEGFR2 is then available to bind VEGF-A, resulting in increased response. Indeed we found that endothelial cells incubated with active MMP-1 had higher mRNA and protein levels of VEGFR2. Furthermore, VEGF-A-dependent phosphorylation of intracellular signaling molecules and endothelial proliferation were elevated after MMP-1 treatment. MMP-1 caused activation of the nuclear factor-κB (NF-κB) pathway (p65/RelA) in endothelial cells, and this response was dependent upon activation of protease activated receptor-1 (PAR-1). Chromatin immunoprecipitation was used to confirm NF-κB-mediated active transcription of the VEGFR2 (KDR) gene. Elevation in VEGFR2 after MMP-1 stimulation was inhibited by PAR-1 knockdown and NF-κB specific inhibition. We conclude that MMP-1 promotes VEGFR2 expression and proliferation of endothelial cells through stimulation of PAR-1 and activation of NF-κB. These results suggest a mechanism by which MMP-1 may prime or sensitize endothelial cell functions.
Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Regulação Enzimológica da Expressão Gênica , Metaloproteinase 1 da Matriz/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Animais , Bovinos , Proliferação de Células , Células Endoteliais/citologia , Humanos , Microscopia de Fluorescência/métodos , Modelos Biológicos , NF-kappa B/metabolismo , Transdução de Sinais , Regulação para CimaRESUMO
We report the case of a 66-year-old man who had been emergently transferred to our institution with hemoptysis and hemodynamic instability. His computed tomography findings were consistent with the presence of an aortobronchial fistula. The patient had undergone open repair of coarctation of aorta via thoracotomy 20 years previously, and he was not deemed a suitable candidate for open repair. He was successfully treated with thoracic endovascular aortic repair with successful exclusion of the fistula. The patient was discharged home, and the subsequent follow-up imaging study at 12 months showed the graft in a stable position without evidence of infection, pseudoaneurysm, or endoleak. This case has demonstrated the successful use of thoracic endovascular aortic repair for urgent management of an aortobronchial fistula.
RESUMO
OBJECTIVES: This study aims to compare veterans and non-veterans undergoing transcatheter aortic valve replacement (TAVR) using data from the Society for Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) registry. METHODS: Patients undergoing TAVR at George Washington University (GWU) and veterans treated at Washington DC Veterans Affairs Medical Center (VAMC) who underwent TAVR at GWU from 2014-2020 were included. All patients were reported in the TVT registry. Emergency and valve-in-valve TAVR were excluded. Cohorts were divided based on veteran status. Operators were the same for both groups. Outcomes were compared at 30 days and 1 year. The primary outcome was mortality and secondary outcomes were morbidity metrics. RESULTS: A total of 299 patients (91 veterans, 208 non-veterans) were included. Veterans had higher rates of hypertension (87.9% vs 77.9%; P=.04), diabetes (46.7% vs 28.9%; P<.01), and lung disease (2.4% vs 11.0%; P<.001). Outcomes were not significantly different between veterans and non-veterans, including 30-day mortality (0% vs 2.9%, respectively; P=.18), 1-year mortality (9.8% vs 10.7%, respectively; P=.61), stroke incidence (0% vs 2.5%, respectively; P=.73), median intensive care unit stay (24 hours in both groups), and overall hospital stay (2 days in both groups). CONCLUSIONS: The affiliation between a VAMC and an academic medical center allowed for direct comparison between veterans and non-veterans undergoing TAVR by the same operators using the TVT registry. Despite significantly higher rates of comorbidities, veterans had equivalent outcomes compared with non-veterans. This may be in part due to the comprehensive care that veterans receive in the VAMC and this institution's integrated heart center team.
Assuntos
Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/cirurgia , Humanos , Sistema de Registros , Fatores de Risco , Substituição da Valva Aórtica Transcateter/efeitos adversos , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Venous hypertension is associated with microvascular inflammation, restructuring, and apoptosis, but the cellular and molecular mechanisms underlying these events remain uncertain. In the present study, we tested the hypothesis that elevated venous pressure and reduction of shear stress induce elevated enzymatic activity. This activity in turn may affect endothelial surface receptors and promote their dysfunction. Using a rodent model for venous hypertension using acute venular occlusion, microzymographic techniques for enzyme detection, and immunohistochemistry for receptor labeling, we found increased activity of the matrix metalloproteases (MMPs) -1, -8, and -9 and tissue inhibitors of metalloproteases (TIMPs) -1 and -2 in both high- and low-pressure regions. In this short time frame, we also observed that elevated venule pressure led to two different fates for the vascular endothelial growth factor receptor-2 (VEGFR2); in higher-pressure upstream regions, some animals exhibited higher VEGFR2 expression, while others displayed lower levels upstream compared to their downstream counterparts with lower pressure. VEGFR2 expression was, on average, more pronounced upon application of MMP inhibitor, suggesting possible cleavage of the receptor by activated enzymes in this model. We conclude that venous pressure elevation increases enzymatic activity which may contribute to inflammation and endothelial dysfunction associated with this disease by influencing critical surface receptors.
Assuntos
Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Metaloproteinases da Matriz/metabolismo , Oclusão Vascular Mesentérica/enzimologia , Veias Mesentéricas/enzimologia , Animais , Biocatálise/efeitos dos fármacos , Dipeptídeos/farmacologia , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Hipertensão/enzimologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Leucócitos/enzimologia , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz , Oclusão Vascular Mesentérica/metabolismo , Oclusão Vascular Mesentérica/fisiopatologia , Veias Mesentéricas/metabolismo , Veias Mesentéricas/fisiopatologia , Ratos , Ratos Wistar , Reperfusão , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Vênulas/enzimologia , Vênulas/metabolismo , Vênulas/fisiopatologiaRESUMO
Chronic venous disease (CVD) has a range of clinical presentations, including tortuous, distended veins in lower extremities, increasing skin pigmentation, and in severe cases ulceration of the affected skin. Venous insufficiency, a precursor to CVD characterized by improper return of blood from the lower extremities to the heart, must be studied in its earliest stages at a time when preventative measures could be applied in man. This underscores the need for basic research into biomarkers and genetic predisposing factors affecting the progression of venous disease. Investigation over the past decade has yielded insight into these specific genetic, cellular and molecular mechanisms underlying the development of venous disease. Among the many advances include the elucidation of an increasing role for matrix metalloproteinases as important mediators of the degenerative process involved with venous insufficiency. This may be preceded by an inflammatory process which further contributes to venular degeneration and endothelial dysfunction seen in advanced presentation of disease. Furthermore, genomic analyses have shed light upon temporal expression patterns of matrix remodeling proteins in diseased tissue samples. In this review we examine some of the current findings surrounding cellular, molecular and genetic advances in delineating the etiology of chronic venous disease.