Effect of aneurysm on biomechanical properties of “radially-oriented” collagen fibers in human ascending thoracic aortic media

We recently reported a mechanistic model to link micro-architectural information to the delamination strength (S_d) of human ascending thoracic aorta (ATA). That analysis demonstrated that the number density (N) and failure energy (U_f) of the radially-oriented collagen fibers contribute to the S_d of both aneurysmal (ATAA) and non-aneurysmal (CTRL-ATA) aortic tissue. Among the set of ATAA samples, we studied specimens from patients displaying bicuspid (BAV) and tricuspid aortic valve (TAV) morphologic phenotypes. Results from our prior work were based on the assumption that the U_f was independent of dissection direction. In the current study, we excluded that assumption and hypothesized that U_f correlates with the S_d of ATAA. To test the hypothesis, we used previously-reported experimentally-determined S_d measurements and N of radially-oriented collagen fibers as input in our validated mechanistic model to calculate U_f for BAV-ATAA, TAV-ATAA and CTRL-ATA tissue specimens. The results of our analysis revealed that U_f is significantly lower for both BAV-ATAA and TAV-ATAA compared to CTRL-ATA cases, and does not differ between BAV-ATAA and TAV-ATAA. Furthermore, we found that U_f is consistent between circumferential-radial and longitudinal-radial planes in either of BAV-ATAA, TAV-ATAA or CTRL-ATA specimens. These findings employ a novel mechanistic model to increase our understanding of the putative interrelationship between biomechanical properties, extracellular matrix biology, and failure energy of aortic dissection.     

The effects of stent interaction on porcine urinary bladder matrix employed as stent-graft materials

Deployment of stent-grafts, derived from synthetic biomaterials, is an established minimally invasive approach for effectively treating abdominal aortic aneurysms (AAAs). However, a notable disadvantage associated with this surgical technique is migration of the deployed stent-graft due to poor biocompatibility and inadequate integration in vivo. Recently, tissue-engineered extracellular matrices (ECMs) have shown early promise as integrating stabilisation collars in this setting due to their ability to induce a constructive tissue remodelling response after in vivo implantation. In the present study the effects of stent loading on an ECM?s mechanical properties were investigated by characterising the compression and loading effects of endovascular stents on porcine urinary bladder matrix (UBM) scaffolds. Results demonstrated that the maximum stress was induced when the stent force was 8-times higher than a standard commercially available stent-graft and this represented about 20% of the failure strength of the UBM material. In addition, the influence of stent shape was also investigated. Findings demonstrated that the stress induced was higher for circular stents at low forces and a higher stress was induced on square stents when increased force was applied. Our findings demonstrate that porcine UBM possesses sufficient mechanical strength to withstand the compression and loading effects of commercially available stent-grafts in the setting of endovascular aneurysm repair.     

Disruption of TGF-β signaling in smooth muscle cell prevents elastase-induced abdominal aortic aneurysm

Transforming growth factor-β (TGF-β) signaling has been significantly implicated in the pathogenesis of aneurysm, prominently the initiation and progression of abdominal aortic aneurysm (AAA). Vascular smooth muscle cell (SMC) is the principal resident cell in aortic wall and is essential for its structure and function. However, the role of TGF-β pathway in SMC for the formation of AAA remains unknown. Therefore, the goal of the present study was to investigate the effect of TGF-β pathway in SMC for AAA pathogenesis, by using a genetical smooth muscle-specific (SM-specific) TGF-βtype II receptor (Tgfbr2) disruption animal model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2^f/f and MyhCre.Tgfbr2^WT/f) and their corresponding wild-type background mice (MyhCre.Tgfbr2^WT/WT) underwent AAA induction by infrarenal peri-adventitial application of elastase. Fourteen days after elastase treatment, the aortas were analyzed and indicated that disruption of 1 or 2 alleles of Tgfbr2 in SMC provided markedly step-wise protection from AAA formation. And elastin degradation, medial SMC loss, macrophage infiltration, and matrix metalloproteinases (MMP) expression were all significantly reduced in Tgfbr2 deletion mice. Our study demonstrated, for the first time, that the TGF-β signaling pathway in SMC plays a critical role in AAA and disruption can prevent the aneurysm formation.     

Midkine exacerbates pressure overload-induced cardiac remodeling

Midkine is a multifunctional growth factor, and its serum levels are increased with the functional severity of heart failure. This study aimed to examine the role of midkine in heart failure pathogenesis. Midkine expression levels were increased in the kidney and lung after transverse aortic constriction (TAC) surgery, but not sufficiently increased in the heart. After TAC, phosphorylation of extracellular signal-regulated kinase1/2 and AKT, and the expression levels of foetal genes in the heart were considerably increased in transgenic mice with cardiac-specific overexpression of midkine (MK-Tg) compared with wild-type (WT) mice. MK-Tg mice showed more severe cardiac hypertrophy and dysfunction, and showed lower survival rate after TAC than WT mice. We conclude that midkine plays a critical role in cardiac hypertrophy and remodelling.     

FHL1在胸主动脉瘤发病机制中的初步研究

目的:研究FHL1蛋白在胸主动脉瘤发病机制中的作用。方法:利用Western Blotting分析胸主动脉瘤患者与正常人主动脉组织中FHL1蛋白表达的情况,利用免疫组织化学检测FHL1蛋白在主动脉组织中的定位,并进一步分析该蛋白在两组中的表达情况,结合文献报道分析FHL1蛋白在胸主动脉瘤发病机制中的作用。结果:Western Blotting、免疫组织化学分析均表明FHL1蛋白在胸主动脉瘤患者主动脉组织表达水平较正常人明显降低,FHL1蛋白主要定位于主动脉血管平滑肌细胞的细胞质中。结论:FHL1蛋白在胸主动脉瘤患者主动脉组织中明显降低,这可能导致主动脉血管平滑肌细胞增殖能力下降,从而在胸主动脉瘤的发病中发挥重要的作用。     

Cardiovascular malformations with normal smooth muscle differentiation in neural crest-specific type II TGFbeta receptor (Tgfbr2) mutant mice

Previous studies have demonstrated that TGFbeta induces a smooth muscle fate in primary neural crest cells in culture. By crossing a conditional allele of the type II TGFbeta receptor with the neural crest-specific Wnt1cre transgene, we have addressed the in vivo requirement for TGFbeta signaling in smooth muscle specification and differentiation. We find that elimination of the TGFbeta receptor does not alter neural crest cell specification to a smooth muscle fate in the cranial or cardiac domains, and that a smooth muscle fate is not realized by trunk neural crest cells in either control or mutant embryos. Instead, mutant embryos exhibit with complete penetrance two very specific and mechanistically distinct cardiovascular malformations--persistent truncus arteriosus (PTA) and interrupted aortic arch (IAA-B). Pharyngeal organ defects such as those seen in models of DiGeorge syndrome were not observed, arguing against an early perturbation of the cardiac neural crest cell lineage. We infer that TGFbeta is an essential morphogenic signal for the neural crest cell lineage in specific aspects of cardiovascular development, although one that is not required for smooth muscle differentiation.     

MicroRNA‐203 mimics age‐related aortic smooth muscle dysfunction of cytoskeletal pathways

Increased aortic stiffness is a biomarker for subsequent adverse cardiovascular events. We have previously reported that vascular smooth muscle Src‐dependent cytoskeletal remodelling, which contributes to aortic plasticity, is impaired with ageing. Here, we use a multi‐scale approach to determine the molecular mechanisms behind defective Src‐dependent signalling in an aged C57BL/6 male mouse model. Increased aortic stiffness, as measured in vivo by pulse wave velocity, was found to have a comparable time course to that in humans. Bioinformatic analyses predicted several miRs to regulate Src‐dependent cytoskeletal remodelling. qRT‐PCR was used to determine the relative levels of predicted miRs in aortas and, notably, the expression of miR‐203 increased almost twofold in aged aorta. Increased miR‐203 expression was associated with a decrease in both mRNA and protein expression of Src, caveolin‐1 and paxillin in aged aorta. Probing with phospho‐specific antibodies confirmed that overexpression of miR‐203 significantly attenuated Src and extracellular signal regulated kinase (ERK) signalling, which we have previously found to regulate vascular smooth muscle stiffness. In addition, transfection of miR‐203 into aortic tissue from young mice increased phenylephrine‐induced aortic stiffness ex vivo, mimicking the aged phenotype. Upstream of miR‐203, we found that DNA methyltransferases (DNMT) 1, 3a, and 3b are also significantly decreased in the aged mouse aorta and that DNMT inhibition significantly increases miR‐203 expression. Thus, the age‐induced increase in miR‐203 may be caused by epigenetic promoter hypomethylation in the aorta. These findings indicate that miR‐203 promotes a re‐programming of Src/ERK signalling pathways in vascular smooth muscle, impairing the regulation of stiffness in aged aorta.     

End stage renal disease‐induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived‐matrix vesicles

Patients with end‐stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4‐fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8‐fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP‐1, and LAMP‐2 and a concomitant up‐regulation of the Annexin family of calcium‐binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC‐derived MVs (51.9‐fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up‐regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC‐derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co‐localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC‐derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.     

胸外科患者术后医院感染的病原菌与危险因素分析

目的:分析胸外科患者术后医院感染的病原菌分布及危险因素,为防控医院感染提供数据支持。方法:选择2014年1月至2015年5月医院接受胸外科手术治疗的患者284例进行研究。回顾性分析284例患者的临床病历数据资料以及细菌培养与鉴定的结果,分析医院感染的主要部位及病原菌分布,以及产生医院感染的危险因素。结果:284例患者共有82例发生医院感染,感染率是28.87%,感染部位以呼吸系统为主,占56.10%;检出病原菌88株,革兰阴性菌71株,占80.68%,以铜绿假单胞菌为主,占30.68%。革兰阳性菌17株,占19.32%,以金葡菌为主,占9.09%。单因素分析发现,胸外科术后医院感染与年龄、手术时间、住院时间及糖尿病史有关,差异有统计学意义(P0.05);Logistic回归分析显示,年龄≥60岁、手术时间2 h、住院时间15 d以及有糖尿病史是胸外科术后医院感染的危险因素。结论:胸外科患者术后医院感染的病原菌分布以铜绿假单胞菌与金葡菌为主,应重点防范影响感染的危险因素,以降低感染率。