RESUMEN
OBJECTIVE: This study aimed to investigate the effect of the soluble Klotho (sKlotho)/Wnt/ß-catenin signaling pathway on vascular calcification in rat models of chronic kidney disease (CKD) and the intervention effect of Shenyuan granules. METHODS: Rats with 5/6 nephrectomy and high phosphorus feeding were used to establish the vascular calcification model. The rats were given gradient doses of Shenyuan granules aqueous solution and calcitriol solution by gavage for 8 weeks, which were divided into experimental group and positive control group. RESULTS: The 5/6 nephrectomy combined with high phosphorus feeding induced thoracic aortic calcification in rats. Shenyuan granules intervention increased the serum sKlotho level, inhibited the mRNA and protein expression of Wnt1, ß-catenin, and Runx2 in the thoracic aorta, and alleviated thoracic aortic media calcification in rats. CONCLUSION: Shenyuan granules may partially regulate the Wnt/ß-catenin signaling pathway via serum sKl to interfere with the expression of Runx2, thereby improving vascular calcification in CKD.
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Medicamentos Herbarios Chinos , Glucuronidasa , Proteínas Klotho , Insuficiencia Renal Crónica , Calcificación Vascular , Vía de Señalización Wnt , beta Catenina , Animales , Masculino , Ratas , Aorta Torácica/metabolismo , Aorta Torácica/patología , beta Catenina/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Glucuronidasa/metabolismo , Glucuronidasa/genética , Proteínas Klotho/metabolismo , Nefrectomía , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/complicaciones , Calcificación Vascular/metabolismo , Calcificación Vascular/etiología , Calcificación Vascular/patología , Vía de Señalización Wnt/efectos de los fármacos , Proteína Wnt1/metabolismo , Proteína Wnt1/genéticaRESUMEN
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.
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Angiotensina II , Ratones Noqueados , Receptor de Angiotensina Tipo 1 , Remodelación Vascular , Animales , Angiotensina II/farmacología , Angiotensina II/metabolismo , Ratones , Masculino , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 1/genética , Femenino , Aorta Torácica/metabolismo , Aorta Torácica/patologíaRESUMEN
Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.
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Adipoquinas , Aneurisma de la Aorta Torácica , Complemento C3a , Fibrilina-1 , Síndrome de Marfan , Receptores de Complemento , Animales , Femenino , Humanos , Masculino , Ratones , Adipoquinas/genética , Aorta Torácica/patología , Aneurisma de la Aorta Torácica/prevención & control , Aneurisma de la Aorta Torácica/etiología , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Complemento C3a/antagonistas & inhibidores , Complemento C3a/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Fibrilina-1/genética , Mediadores de Inflamación/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Síndrome de Marfan/complicaciones , Síndrome de Marfan/genética , Síndrome de Marfan/tratamiento farmacológico , Ratones Endogámicos C57BL , Receptores de Complemento/antagonistas & inhibidores , Receptores Acoplados a Proteínas G , Transducción de SeñalRESUMEN
BACKGROUND: This study aims to identify a morphological indicator of aortic dissection (AD) based on the geometrical characteristics of the thoracic aorta. METHODS: We evaluated computed tomographic angiograms of 63 samples with AD (22 with type A AD, 41 with type B AD) and 71 healthy samples. Via centerline extraction and spatial transformation, the spatial entanglement of the aorta was minimized, and the expanded 2D aortic morphology was obtained. The 2D morphology of the thoracic aorta was fit to a circle. The applicability of the fitting circle method for identifying aortic dissection was verified by multivariable logistic regression analysis. RESULTS: Via the 3D coordinate transformation algorithm, the optimal aortic view was obtained. On this view, the geometrical characteristics of the thoracic aortas of the healthy controls were similar to a portion of a circle (sum of residuals: 3502.45 ± 2566.71, variance: 86.23 ± 56.60), while that of AD samples had poorer similarity to the circle (sum of residuals: 5404.78 ± 3891.69, variance: 129.90 ± 90.09). This difference was significant (p < 0.001). A logistic regression model showed that increased deformation of the thoracic aorta was a significant indicator of aortic dissection (odds ratio: 1.35, p = 0.034). CONCLUSIONS: The morphology of the healthy thoracic aorta could be fit to a circle, while that of the dissected aorta had poorer similarity to the circle. The statistics of the circle are an effective indicator of aortic deformation in AD. TRIAL REGISTRATION: This study is registered in the Chinese Clinical Trial Registry (ChiCTR2000029219).
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Aorta Torácica , Aneurisma de la Aorta Torácica , Disección Aórtica , Aortografía , Angiografía por Tomografía Computarizada , Valor Predictivo de las Pruebas , Interpretación de Imagen Radiográfica Asistida por Computador , Humanos , Disección Aórtica/diagnóstico por imagen , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/patología , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios de Casos y Controles , Adulto , Estudios Retrospectivos , Tomografía Computarizada MultidetectorRESUMEN
The anatomical features spanning from the aortic arch to the proximal carotid artery and the associated cardiovascular risks might significantly influence the development of right carotid plaque. Our research aimed to compare these anatomical and risk factors between individuals with no carotid plaque and those with moderate right-side carotid plaque within a Korean cohort. We conducted a retrospective, cross-sectional analysis involving 413 participants, categorized into a normal group (n = 339) and a right moderate carotid plaque group (defined as > 50% stenosis based on NASCET criteria) (n = 74). We collected data on cardiovascular risk factors and conducted laboratory tests. A 3D model of the carotid artery was constructed using cranio-cervical computed tomography angiography (CTA) data through semi-automated software. Measurements taken on this 3D model included the common carotid artery (CCA), internal carotid artery (ICA), external carotid artery (ECA), and carotid artery bifurcation (CAB) in terms of maximal vascular diameter, sectional area, angles of carotid bifurcation and ICA, and carotid tortuosity. When compared with the normal group, individuals in the right moderate carotid plaque group exhibited smaller angles at the carotid bifurcation, larger CCA diameter and sectional area (p < 0.01), advanced age, and a higher incidence of hypertension, diabetes, and stroke history (p < 0.05), along with reduced glomerular filtration rate (GFR) (p < 0.001). Multivariate analysis revealed that the sectional area of the bifurcation, calcification of the aortic bulb, and GFR were independently associated with the presence of right moderate carotid plaque (p < 0.01). Statistical analyses disclosed significant differences in both clinical risk factors and geometric changes in the region extending from the aortic arch to the proximal carotid artery among subjects with right moderate carotid plaque when compared to those without.
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Aorta Torácica , Arteria Carótida Interna , Angiografía por Tomografía Computarizada , Humanos , Masculino , Femenino , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/patología , Persona de Mediana Edad , Anciano , Factores de Riesgo , Estudios Retrospectivos , Estudios Transversales , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/patología , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/patología , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/patologíaRESUMEN
BACKGROUND: Women with thoracic aortic aneurysms within the arch or descending thoracic aorta have poorer survival than men. Sex differences in relative thoracic aortic aneurysm size may account for some of the discrepancy. The aim of this study was to explore whether basing clinical management on aneurysm size index (maximum aneurysm diameter/body surface area) rather than aneurysm size can restore equality of survival by sex. METHODS: The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA; ISRCTN04044627) study was a prospective, observational cohort study. Adults referred to National Health Service hospitals in England with new/existing arch or descending thoracic aorta aneurysms greater than or equal to 4 cm in diameter were followed from March 2014 to March 2022. Baseline characteristics and survival to intervention and overall were compared for men and women. Survival models were used to assess the association between all-cause survival and sex, with and without adjustment for aneurysm diameter or aneurysm size index. RESULTS: A total of 886 thoracic aortic aneurysm patients were recruited: 321 (36.2%) women and 565 (63.8%) men. The mean(s.d.) aneurysm diameter was the same for women and men (5.7(1.1) versus 5.7(1.2) cm respectively; P = 0.751), but the mean(s.d.) aneurysm size index was greater for women than for men (3.32(0.80) versus 2.83(0.63) respectively; P < 0.001). Women had significantly worse survival without intervention: 110 (34.3%) women and 135 (23.9%) men (log rank test, P < 0.001). All-cause mortality remained greater for women after adjustment for diameter (HR 1.65 (95% c.i. 1.35 to 2.02); P < 0.001), but was attenuated after adjustment for aneurysm size index (HR 1.11 (95% c.i. 0.89 to 1.38); P = 0.359). Similar results were found for all follow-up, with or without intervention, and findings were consistent for descending thoracic aorta aneurysms alone. CONCLUSION: Guidelines for referral to specialist services should consider including aneurysm size index rather than diameter to reduce inequity due to patient sex.
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Aneurisma de la Aorta Torácica , Humanos , Aneurisma de la Aorta Torácica/mortalidad , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/terapia , Femenino , Masculino , Anciano , Estudios Prospectivos , Persona de Mediana Edad , Inglaterra/epidemiología , Factores Sexuales , Disparidades en Atención de Salud/estadística & datos numéricos , Aorta Torácica/patologíaAsunto(s)
Aorta Torácica , Aneurisma de la Aorta Torácica , Síndrome de Marfan , Músculo Liso Vascular , Miocitos del Músculo Liso , Proteómica , Síndrome de Marfan/metabolismo , Síndrome de Marfan/complicaciones , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Humanos , Aorta Torácica/metabolismo , Aorta Torácica/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/efectos de los fármacos , Células Cultivadas , AnimalesRESUMEN
OBJECTIVES: Interruption of aortic arch (IAA) is a rare congenital heart disease. This study aims to investigate echocardiographic features and pathological ultrastructural characteristics of fetal IAA and to further analyze its pathological evolution. METHODS: A retrospective analysis was conducted on prenatal echocardiographic, post-surgical, or autopsy findings of fetuses prenatally diagnosed with IAA. Prenatal echocardiographic tracking was used to observe the internal diameters and Z-scores of different segments of the aortic arch and the changes in the narrowed section. These observations were combined with autopsy and pathological findings to explore the potential intrauterine evolution of IAA and its cytological basis. RESULTS: The study included 34 fetuses with IAA, with 3, 3, and 28 fetuses prenatally diagnosed with aortic arch dysplasia (AAD), coarctation of aorta (CoA), and IAA, respectively. The 3 AAD and 3 CoA fetuses chose termination of pregnancy 1 to 2 weeks after prenatal ultrasound diagnosis, and autopsy confirmed IAA. Among the 28 fetuses prenatally diagnosed with IAA, 6 cases of CoA progressively worsened, eventually evolving into type A IAA as observed through echocardiographic follow-up. The remaining 22 cases were diagnosed as IAA on the first prenatal ultrasound. Postnatal surgery corrected 3 cases, while 27 cases opted for pregnancy termination, and 4 cases resulted in intrauterine death. Echocardiographic features of the fetal IAA included a significantly smaller left ventricle compared with the right or negligible difference on the four-chamber view, a significantly smaller aorta than the pulmonary artery on the three-vessel view, and a lack of connection between the aorta and the descending aorta on the three-vessel-trachea and aortic arch views. The aortic arch appears less curved and more rigid, losing the normal "V" shape between the aorta, ductus arteriosus, and descending aorta. Color Doppler ultrasound showed no continuous blood flow signal at the interruption site, with reversed blood flow visible in the ductus arteriosus. Transmission electron microscopy of 7 IAA fetuses revealed numerous disorganized smooth muscle cells between the elastic membranes near the aortic arch interruption site, significantly increased in number compared with the proximal ascending aorta. The elastic membranes were thicker and more twisted near the interruption site. The interruption area lacked normal endothelial cells and lumen, with only remnants of necrotic endothelial cells, disorganized short and thick elastic membranes, and randomly arranged smooth muscle cells. CONCLUSIONS: Prenatal echocardiography is the primary diagnostic tool for fetal IAA. Post-surgical follow-up and autopsy help identify complications and disease characteristics, enhancing diagnostic accuracy. Some fetal IAA may evolve from AAD or CoA, with potential pathogenesis related to ischemia, hypoxia, and migration of ductal constrictive components.
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Aorta Torácica , Ultrasonografía Prenatal , Humanos , Femenino , Aorta Torácica/embriología , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/patología , Embarazo , Estudios Retrospectivos , Ecocardiografía , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/embriología , Coartación Aórtica/diagnóstico por imagen , Coartación Aórtica/patología , Coartación Aórtica/embriología , AdultoRESUMEN
BACKGROUND: Cellular communication among different types of vascular cells is indispensable for maintaining vascular homeostasis and preventing atherosclerosis. However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat atherosclerosis remain unknown. We hypothesized that endothelial autophagy mediates the cellular communication in vascular tissue through exosome-mediated delivery of atherosclerosis-related genes. METHODS: Rapamycin and adeno-associated virus carrying Atg7 short hairpin RNA under the Tie (TEK receptor tyrosine kinase) promoter were used to activate and inhibit vascular endothelial autophagy in high-fat diet-fed ApoE-/- mice, respectively. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue were used to explore the effects of endothelial autophagy on endothelial function and atherosclerosis and its molecular mechanisms. Quantitative polymerase chain reaction and miRNA sequencing were performed to determine changes in miRNA expression in exosomes. Immunofluorescence and exosome coculture experiments were conducted to examine the role of endothelial autophagy in regulating the communication between endothelial cells and smooth muscle cells (SMCs) via exosomal miRNA. RESULTS: Endothelial autophagy was inhibited in thoracic aortas of high-fat diet-fed ApoE-/- mice. Furthermore, rapamycin alleviated high-fat diet-induced atherosclerotic burden and endothelial dysfunction, while endothelial-specific Atg7 depletion aggravated the atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments, and human vascular tissue analysis revealed that miR-204-5p was significantly increased in endothelial cells after high-fat diet exposure, which directly targeted Bcl2 to regulate endothelial cell apoptosis. Importantly, endothelial autophagy activation decreased excess miR-204-5p by loading miR-204-5p into multivesicular bodies and secreting it through exosomes. Moreover, exosomal miR-204-5p can effectively transport to SMCs, alleviating SMC calcification by regulating target proteins such as RUNX2 (runt-related transcription factor 2). CONCLUSIONS: Our study revealed the exosomal pathway by which endothelial autophagy protects atherosclerosis: endothelial autophagy activation transfers miR-204-5p from endothelial cells to SMCs via exosomes, both preventing endothelial apoptosis and alleviating SMC calcification. REGISTRATION: URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2200064155.
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Aterosclerosis , Autofagia , Comunicación Celular , Modelos Animales de Enfermedad , Exosomas , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , MicroARNs , Miocitos del Músculo Liso , MicroARNs/metabolismo , MicroARNs/genética , Exosomas/metabolismo , Exosomas/genética , Animales , Aterosclerosis/patología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Humanos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Masculino , Ratones , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Proteína 7 Relacionada con la Autofagia/metabolismo , Proteína 7 Relacionada con la Autofagia/genética , Células Cultivadas , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Placa Aterosclerótica , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/prevención & control , Enfermedades de la Aorta/metabolismo , Técnicas de Cocultivo , Transducción de Señal , Aorta Torácica/metabolismo , Aorta Torácica/patología , Dieta Alta en GrasaRESUMEN
The underlying molecular mechanisms of thoracic aortic dissection (TAD) remain incompletely understood. Recent insights into RNA methylation and microRNA-mediated gene regulation offer new avenues for exploring how these processes contribute to the pathophysiology of TAD, particularly through the modulation of pyroptosis and smooth muscle cell viability. This research aimed to elucidate the interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis, a mechanism implicated in the pathogenesis of TAD. We collected tissue samples from 28 human TAD patients and 8 healthy aortic group, as well as utilized a mouse model to replicate the disease. A combination of computational, in vitro, and in vivo methods was applied, including CIBERSORTx analysis, Pearson correlation, gene transfection using antagomiR-16-5p, siRNA, and several staining as well as cell culture techniques. Our analysis indicated two differentially expressed genes, ALKBH2 and YTHDC1. We found significant upregulation of has-miR-16-5p and downregulation of YTHDC1 at mRNA level in AD samples. Immune cell infiltration in TAD samples was examined using the CIBERSORTx database. We confirmed that YTHDC1 was a target of miR-16-5p, as evidenced by an inhibitory effect on luciferase activity. Inhibition of miR-16-5p enhanced SMC proliferation and promoted cell viability whilst downregulating NLRP3-pyroptosis. YTHDC1 expression was increased, and NLRP3-pyroptosis expressions were inhibited, suggesting miR-16-5p/YTHDC1 axis may involve the NLRP3-pyroptosis of the SMC. In vivo analyses confirmed the prevention of NLRP3-pyroptosis in middle layer of the thoracic aorta, implying that the miR-16-5p/YTHDC1 axis regulated SMC proliferation via NLRP3-pyroptosis signaling. Our findings underscored the anti-pyroptotic role of miR-16-5p/YTHDC1 axis in the pathogenesis of TAD, suggesting a potential therapeutic strategy via targeting YTHDC1 and suppressing miR-16-5p to inhibit NLRP3-dependent pyroptosis. Although further investigation is needed, these results relating to SMC proliferation are a significant step forward in understanding TAD.
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Disección de la Aorta Torácica , MicroARNs , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Femenino , Humanos , Masculino , Ratones , Aorta Torácica/patología , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/patología , Modelos Animales de Enfermedad , Disección de la Aorta Torácica/genética , Disección de la Aorta Torácica/patología , Regulación de la Expresión Génica , MicroARNs/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Piroptosis/genética , Transducción de SeñalRESUMEN
Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.
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Aorta Torácica , Válvula Aórtica , Humanos , Aorta Torácica/anomalías , Aorta Torácica/patología , Válvula Aórtica/anomalías , Válvula Aórtica/patología , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Enfermedad de la Válvula Aórtica Bicúspide/genética , Estenosis de la Válvula Pulmonar/genética , Mutación , Receptor Notch1/genética , Enfermedad de la Válvula Aórtica/genética , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/patología , Calcinosis/genética , Calcinosis/patología , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/patología , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/patologíaRESUMEN
Perivascular adipose tissue (PVAT) is an adipose layer, surrounding blood vessels, with a local modulatory role. Interleukin-10 (IL-10) has been shown to modulate vascular tissue. This study aimed to characterize the endogenous role of IL-10 in vascular remodeling, and PVAT phenotyping. Thoracic aortic segments from control (C57BL/6J) and IL-10 knockout (IL-10-/-) male mice were used. Analyzes of aorta/PVAT morphometry, and elastin, collagen and reticulin deposition were performed. Tissue uncoupling protein 1 (UCP1) was accessed by Western blotting. Endogenous absence of IL-10 reduced total PVAT area (p = 0.0310), and wall/lumen ratio (p = 0.0024), whereas increased vascular area and thickness (p < 0.0001). Total collagen deposition was augmented in IL-10-/-, but under polarized light, the reduction of collagen-I (p = 0.0075) and the increase of collagen-III (p = 0.0055) was found, simultaneously with reduced elastic fibers deposition (p = 0.0282) and increased deposition of reticular fibers (p < 0.0001). Adipocyte area was augmented in the IL-10 absence (p = 0.0225), and UCP1 expression was reduced (p = 0.0420). Moreover, relative frequency of white adipose cells and connective tissue was augmented in IL-10-/- (p < 0.0001), added to a reduction in brown adipose cells (p < 0.0001). Altogether, these data characterize aorta PVAT from IL-10-/- as a white-like adipocyte phenotype. Endogenous IL-10 prevents vascular remodeling and favors a brown-like adipocyte phenotype, suggesting a modulatory role for IL-10 in PVAT plasticity.
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Tejido Adiposo Blanco , Interleucina-10 , Ratones Endogámicos C57BL , Ratones Noqueados , Remodelación Vascular , Animales , Interleucina-10/metabolismo , Interleucina-10/genética , Remodelación Vascular/genética , Masculino , Ratones , Tejido Adiposo Blanco/metabolismo , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Aorta Torácica/metabolismo , Aorta Torácica/patología , Colágeno/metabolismo , Tejido Adiposo/metabolismoRESUMEN
BACKGROUND AND AIMS: The role of aortic mineralization in the pathogenesis of acute type B aortic dissection (TBAD) is unclear. Whether thoracic aortic calcification (TAC) and circulating alkaline phosphatase (ALP) activity are associated with acute TBAD risk remains elusive. METHODS: Observational and Mendelian randomization (MR) studies were conducted sequentially. Using propensity score matching (1:1) by age and sex, patients with acute TBAD (n = 125) were compared with control patients (n = 125). Qualitative (score) and quantitative (volume) analyses of the TAC burden on different thoracic aortic segments were conducted using non-enhanced computed tomography. Univariate and multivariate analyses were used to identify significant independent risk factors for TBAD and TAC burden, respectively. MR was finally used to determine the causal relationship between elevated ALP activity and TBAD risk. RESULTS: The qualitative and quantitative analyses revealed that TAC burden was significantly higher in the TBAD group, except for in the ascending aortic segment (both p < 0.05). Preoperative circulating ALP was significantly elevated in the TBAD group (p < 0.001). The elevated TAC burden score on the descending thoracic aortic segment (odds ratio [OR] 3.31, 95% confidence interval [CI] 1.31-8.37) and increased ALP activity (OR 1.03, 95% CI 1.01-1.06) was independently associated with TBAD risk. Interestingly, ALP was significantly positively associated with TAC burden, and MR analyses confirmed that ALP genetically predicted TBAD risk. CONCLUSIONS: Elevated ALP may trigger TBAD risk via the increased volume of TAC. Aortic mineralization may not protect the aorta itself.
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Fosfatasa Alcalina , Aneurisma de la Aorta Torácica , Disección Aórtica , Análisis de la Aleatorización Mendeliana , Calcificación Vascular , Humanos , Disección Aórtica/diagnóstico por imagen , Disección Aórtica/etiología , Masculino , Femenino , Persona de Mediana Edad , Factores de Riesgo , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/genética , Calcificación Vascular/diagnóstico por imagen , Fosfatasa Alcalina/sangre , Anciano , Enfermedad Aguda , Aorta Torácica/diagnóstico por imagen , Aorta Torácica/patología , Medición de Riesgo , Estudios de Casos y Controles , Biomarcadores/sangre , Aortografía/métodos , Predisposición Genética a la Enfermedad , Angiografía por Tomografía ComputarizadaRESUMEN
Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM-VSMC network.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Músculo Liso Vascular , Miocitos del Músculo Liso , Humanos , Aneurisma de la Aorta Torácica/patología , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/fisiopatología , Disección Aórtica/patología , Disección Aórtica/genética , Disección Aórtica/metabolismo , Animales , Músculo Liso Vascular/patología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/patología , Miocitos del Músculo Liso/metabolismo , Aorta Torácica/patología , Aorta Torácica/fisiopatología , Remodelación Vascular , Matriz Extracelular/patología , Matriz Extracelular/metabolismo , FenotipoRESUMEN
Apigenin and baicalein are structurally related flavonoids that have been reported to have multiple pharmacological activities. The aim of this study was to investigate the protective effects and potential mechanisms of apigenin and baicalein in D-galactose-induced aging rats. First, apigenin and baicalein showed remarkable antioxidant activity and anti-glycation activity in vitro. Secondly, the protective effects of apigenin and baicalein on aging rats were investigated. We found that apigenin and baicalein supplementation significantly ameliorated aging-related changes such as declines in the spatial learning and memory and histopathological damage of the hippocampus and thoracic aorta. In addition, our data showed that apigenin and baicalein alleviated oxidative stress as illustrated by decreasing MDA level, increasing SOD activity and GSH level. Further data showed that they significantly reduced the accumulation of advanced glycation end products (AGEs), inhibited the expression of RAGE, down-regulated phosphorylated nuclear factor (p-NF-κB (p65)). Our results suggested that the protective effects of apigenin and baicalein on aging rats were at least partially related to the inhibition of AGEs/RAGE/NF-κB pathway and the improvement of oxidative damage. Overall, apigenin and baicalein showed almost equal anti-aging efficacy. Our results provided an experimental basis for the application of apigenin and baicalein to delay the aging process.
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Envejecimiento , Aorta Torácica , Apigenina , Flavanonas , Galactosa , Productos Finales de Glicación Avanzada , FN-kappa B , Estrés Oxidativo , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada , Transducción de Señal , Animales , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Flavanonas/farmacología , Flavanonas/uso terapéutico , Apigenina/farmacología , Apigenina/uso terapéutico , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Masculino , FN-kappa B/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/inducido químicamente , Antioxidantes/farmacologíaRESUMEN
Endothelial cells (ECs) in the descending aorta are exposed to high laminar shear stress, and this supports an antiinflammatory phenotype. High laminar shear stress also induces flow-aligned cell elongation and front-rear polarity, but whether these are required for the antiinflammatory phenotype is unclear. Here, we showed that caveolin-1-rich microdomains polarize to the downstream end of ECs that are exposed to continuous high laminar flow. These microdomains were characterized by high membrane rigidity, filamentous actin (F-actin), and raft-associated lipids. Transient receptor potential vanilloid (TRPV4) ion channels were ubiquitously expressed on the plasma membrane but mediated localized Ca2+ entry only at these microdomains where they physically interacted with clustered caveolin-1. These focal Ca2+ bursts activated endothelial nitric oxide synthase within the confines of these domains. Importantly, we found that signaling at these domains required both cell body elongation and sustained flow. Finally, TRPV4 signaling at these domains was necessary and sufficient to suppress inflammatory gene expression and exogenous activation of TRPV4 channels ameliorated the inflammatory response to stimuli both in vitro and in vivo. Our work revealed a polarized mechanosensitive signaling hub in arterial ECs that dampened inflammatory gene expression and promoted cell resilience.
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Calcio , Células Endoteliales , Inflamación , Mecanotransducción Celular , Canales Catiónicos TRPV , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Animales , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Calcio/metabolismo , Ratones , Humanos , Microdominios de Membrana/metabolismo , Caveolina 1/metabolismo , Caveolina 1/genética , Señalización del Calcio , Estrés Mecánico , Aorta Torácica/metabolismo , Aorta Torácica/patologíaRESUMEN
BACKGROUND: ß-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice. METHODS: BAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to BAPN dose, and mouse strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, the ascending and descending thoracic aortas were harvested after 1 week of BAPN administration before the appearance of overt pathology. RESULTS: BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-SMA (α-smooth muscle actin). One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the 2 aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. CONCLUSIONS: BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.
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Aminopropionitrilo , Aorta Torácica , Rotura de la Aorta , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Animales , Aminopropionitrilo/toxicidad , Aminopropionitrilo/farmacología , Aorta Torácica/patología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Femenino , Masculino , Rotura de la Aorta/inducido químicamente , Rotura de la Aorta/patología , Rotura de la Aorta/metabolismo , Rotura de la Aorta/prevención & control , Ratones , Remodelación Vascular/efectos de los fármacos , Dilatación Patológica , Músculo Liso Vascular/patología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Factores de Edad , Factores de Tiempo , Factores Sexuales , Proliferación Celular/efectos de los fármacos , Proteína-Lisina 6-Oxidasa/metabolismoRESUMEN
Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II , Aneurisma de la Aorta , Losartán , Síndrome de Marfan , Transducción de Señal , Ratones , Síndrome de Marfan/tratamiento farmacológico , Síndrome de Marfan/patología , Modelos Animales de Enfermedad , Aneurisma de la Aorta/tratamiento farmacológico , Aneurisma de la Aorta/prevención & control , Oligopéptidos/administración & dosificación , Aorta Torácica/efectos de los fármacos , Aorta Torácica/patología , Pirimidinas/administración & dosificación , Combinación de Medicamentos , Losartán/administración & dosificación , Antagonistas de Receptores de Angiotensina/administración & dosificación , Transducción de Señal/efectos de los fármacos , Humanos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificaciónRESUMEN
BACKGROUND: Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS: Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS: Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION: In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.
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Glucemia , Diabetes Mellitus Experimental , Células Endoteliales de la Vena Umbilical Humana , Canales Iónicos , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III , Estrés Oxidativo , Animales , Humanos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Diabetes Mellitus Experimental/metabolismo , Canales Iónicos/metabolismo , Canales Iónicos/genética , Glucemia/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Mecanotransducción Celular , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/deficiencia , Células Cultivadas , Proliferación Celular , Apoptosis , Masculino , Angiopatías Diabéticas/metabolismo , Angiopatías Diabéticas/fisiopatología , Angiopatías Diabéticas/patología , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/etiología , Movimiento Celular , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Aorta Torácica/metabolismo , Aorta Torácica/patología , Aorta Torácica/fisiopatología , Ratones , Estreptozocina , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Endotelio Vascular/patología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genéticaRESUMEN
ABSTRACT: Vascular calcification (VC), a major complication in chronic kidney disease (CKD), is predominantly driven by osteoblastic differentiation. Recent studies have highlighted the crucial role of microRNAs in CKD's pathogenesis. Here, our research focused on the effects of miR-204-5p and its molecular mechanisms within VC. We initially found a notable decrease in miR-204-5p levels in human aortic vascular smooth muscle cells stimulated with inorganic phosphate, using this as a VC model in vitro. Following the overexpression of miR-204-5p, a decrease in VC was observed, as indicated by alizarin red S staining and measurements of calcium content. This decrease was accompanied by lower levels of the osteogenic marker, runt-related transcription factor 2, and higher levels of α-smooth muscle actin, a marker of contractility. Further investigation showed that calcium/calmodulin-dependent protein kinase 1 (CAMK1), which is a predicted target of miR-204-5p, promotes VC. Conversely, overexpressing miR-204-5p reduced VC by suppressing CAMK1 activity. Overexpressing miR-204-5p also effectively mitigated aortic calcification in an in vivo rat model. In summary, our research indicated that targeting the miR-204-5p/CAMK1 pathway could be a viable strategy for mitigating VC in CKD patients.