T-cadherin upregulation correlates with cell-cycle progression and promotes proliferation of vascular cells

Objective: In vascular tissue, T-cadherin (T-cad) levels correlate with the progression of atherosclerosis, restenosis and tumour neovascularization. This study investigates whether T-cad influences proliferation of vascular cells. Methods and Results: Cultures of human umbilical vein endothelial cells (HUVEC) and rat and human aortic smooth muscle cells (rSMC, hSMC) were used. T-cad was overexpressed in HUVEC and hSMC using an adenoviral expression system. In cultures released from G1/G0 synchrony parallel immunoblot analysis of T-cad and cell cycle phase specific markers (p27Kip1, cyclin D1, E2F1, PCNA, cyclin B) showed increased T-cad protein levels subsequent to entry into early S-phase with sustained elevation through S-and M-phases. T-cad was increased in G2/M-phase (colchicine) synchronized cultures. In FACS-sorted cell populations, expression of T-cad in S-and G2/M-phase was higher than G1/G0-phase. Compared with empty-and LacZ-vector infected controls, HUVEC and hSMC overexpressing T-cad exhibited increased proliferation as assessed in enumeration and DNA synthesis assays. Additionally, following release from G1/G0 synchrony, HUVEC and hSMC overexpressing T-cad enter S-phase more rapidly. Flow cytometry after BrdU/propidium labelling confirmed increased cell cycle progression in T-cad overexpressing cells. Conclusion: In vascular cells, T-cad is dynamically regulated during the cell cycle and its expression functions in the promotion of proliferation. T-cad may facilitate progression of proliferative vascular disorders such as atherosclerosis, restenosis and tumour angiogenesi

Polarisation of T-cadherin to the leading edge of migrating vascular cells in vitro: a function in vascular cell motility?

Both histological and in vitro studies indicate a relationship between T-cadherin levels and acquisition of a modulated, migratory phenotype by vascular cells. This study further examines a role for T-cadherin in relation to cell migration and adhesion. Fluorescence microscopic examination of T-cadherin localisation in confluent cultures of human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells and the human carcinoma cell line ECV-304 revealed global distribution over the entire cell body, and with only slight enrichment at cell borders. This contrasts with restricted cell-cell junction localisation of classical cadherin (for example, VE-cadherin in HUVEC). In wounded cultures, T-cadherin polarised to the leading edge of cells migrating into the wound area, again contrasting with classical VE-cadherin, which was undetectable in this region. Confocal microscopy demonstrated that potential signalling functions of T-cadherin at the leading edge are unrelated to physical interactions with caveolin. Adherence of HUVEC onto a monolayer of T-cadherin-transfected L929 cells is significantly reduced compared with adhesion onto control (T-cadherin-negative) L929. Thus T-cadherin is not required for maintenance of intercellular adhesion, but may rather function as a signalling molecule involved in cell-cell recognition and sensing of the environment in processes where cell detachment occur

ТРАНСПОРТНЫЕ ПОТОКИ АМЕРИКАНСКОЙ АДМИНИСТРАЦИИ ПОМОЩИ (АРА) НА ПРИМЕРЕ ПЕТРОГРАДА (1921-1923 ГГ.)

Purpose. The American Relief Administration (ARA) provided the great humanitarian mission in Russia during the famine in 1921–1923. Wherein the problem of suppling food from the United States to starving people in the vast territories of Russia was successfully fulfiled. The ARA practice remains interesting for modern humanitarian organizations.Methodology. The history of the ARA in Russia is being investigated now, but its work in Petrograd has been almost unexplored. Our paper used the documents from the Russian central and regional archives such as the Central State Archives of St. Petersburg, the The State Archive of the Russian Federation (GARF, Moscow) and published studies.Results. This aspect of aid was studied on the example of Petrograd as the place of first unloading of foreign aid delivered by sea and rail transport, its reloading onto the railroad for transportation to the ARA aid regions. The scheme of food delivery from the ARA to the starving people of Petrograd is considered for the first time.Petrograd received 53,111.8 tons of cargo on 30 ships both directly from the United States and after transshipment in Hamburg. By rail, ARA cargoes arrived in Petrograd from Tallinn, by the way Petrograd recieved some ARA cargoes from Moscow. Deliveries from Petrograd was sent by rail through Moscow and Vologda to the Volga region, the destination stations were Rybinsk and Nizhny Novgorod.The ARA’s relief to the starving population of Petrograd itself was also significant, its total weight was 2947.335 tons, and the cost was $282,210.61.The main places associated with the transportation of goods and food points for the starving population of the city have been identified and shown on the map of Petrograd. Horse-drawn and road transport was used within the city.Practical implications. The materials can be useful for scientific development in the subject of relief of the ARA, in preparation of educational works on Russian history. The results may be of interest to local historians.Цель. Американская администрация помощи (АРА) оказала масштабную гуманитарную помощь России во время голода в 1921–1923 гг. При этом была успешна решена проблема доставки продовольствия из США к голодающим людям на огромных пространствах России. Практика АРА остается актуальной для современных гуманитарных организаций.Метод проведения работы. Деятельность АРА в Петрограде практически не исследована. В статье использованы документы из Центрального государственного архива Санкт-Петербурга, Государственного архива Российской Федерации (Москва) и опубликованные исследования.Результаты. Транспортный аспект помощи АРА изучен на примере Петрограда как места первой разгрузки иностранной помощи, доставленной морским и железнодорожным транспортом, ее перегрузки на железную дорогу для транспортировки к районам оказания помощи АРА. Впервые рассмотрена схема доставки продовольствия от АРА голодающим людям Петрограда.В Петроград поступило 53111,8 т грузов на 30 пароходах как прямо из США, так и после перегрузки в Гамбурге. По Северо-Западным железным дорогам грузы АРА поступали в Петроград из Таллина, некоторые грузы АРА в Петроград доставлялись по железной дороге через Москву. Помощь из Петрограда отправляли по железной дороге через Москву и Вологду в Волжский регион, станциями назначения были Рыбинск и Нижний Новгород.Помощь АРА голодающему населению самого Петрограда также была значительной, ее общий вес составил 2947,335 т, а стоимость – 282210,61$.Установлены и показаны на карте Петрограде основные места, связанные с транспортировкой грузов, и пункты питания для голодающего населения города. Для доставки помощи внутри города использовали гужевой и автомобильный транспорт.Область применения результатов. Материалы работы могут быть использованы для научных обобщений в теме помощи АРА, при подготовке учебных материалов по отечественной истории. Результаты могут заинтересовать краеведов

T-cadherin attenuates insulin-dependent signalling, eNOS activation, and angiogenesis in vascular endothelial cells

Aims T-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin family member. Experimental, clinical, and genomic studies suggest a role for T-cad in vascular disorders such as atherosclerosis and hypertension, which are associated with endothelial dysfunction and insulin resistance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that T-cad is a regulatory component of insulin signalling in EC and therefore a determinant of the development of endothelial InsRes. Methods and results We investigated T-cad-dependent effects on insulin sensitivity using human EC stably transduced with respect to T-cad overexpression or T-cad silencing. Responsiveness to insulin was examined at the level of effectors of the insulin signalling cascade, EC nitric oxide synthase (eNOS) activation, and angiogenic behaviour. Overexpression and ligation of T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely, T-cad silencing enhances these actions of insulin. Attenuation of EC responsiveness to insulin results from T-cad-mediated chronic activation of the Akt/mTOR-dependent negative feedback loop of the insulin cascade and enhanced degradation of the insulin receptor (IR) substrate. Co-immunoprecipitation experiments revealed an association between T-cad and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling, demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and protein levels in EC. Conclusion T-cad expression modulates signalling and functional responses of EC to insulin. We have identified a novel signalling mechanism regulating insulin function in the endothelium and attribute a role for T-cad up-regulation in the pathogenesis of endothelial InsRe

T-cadherin is present on endothelial microparticles and is elevated in plasma in early atherosclerosis

Aims The presence of endothelial cell (EC)-derived surface molecules in the circulation is among hallmarks of endothelial activation and damage in vivo. Previous investigations suggest that upregulation of T-cadherin (T-cad) on the surface of ECs may be a characteristic marker of EC activation and stress. We investigated whether T-cad might also be shed from ECs and in amounts reflecting the extent of activation or damage. Methods and results Immunoblotting showed the presence of T-cad protein in the culture medium from normal proliferating ECs and higher levels in the medium from stressed/apoptotic ECs. Release of T-cad into the circulation occurs in vivo and in association with endothelial dysfunction. Sandwich ELISA revealed negligible T-cad protein in the plasma of healthy volunteers (0.90 ± 0.90 ng/mL, n = 30), and increased levels in the plasma from patients with non-significant atherosclerosis (9.23 ± 2.61 ng/mL, n = 63) and patients with chronic coronary artery disease (6.93 ± 1.31 ng/mL, n = 162). In both patient groups there was a significant (P = 0.043) dependency of T-cad and degree of endothelial dysfunction as measured by reactive hyperaemia peripheral tonometry. Flow cytometry analysis showed that the major fraction of T-cad was released into the EC culture medium and the plasma as a surface component of EC-derived annexin V- and CD144/CD31-positive microparticles (MPs). Gain-of-function and loss-of-function studies demonstrate that MP-bound T-cad induced Akt phosphorylation and activated angiogenic behaviour in target ECs via homophilic-based interactions. Conclusion Our findings reveal a novel mechanism of T-cad-dependent signalling in the vascular endothelium. We identify T-cad as an endothelial MP antigen in vivo and demonstrate that its level in plasma is increased in early atherosclerosis and correlates with endothelial dysfunctio

Prevalence of Risk Factors of Thromboembolic Complications in Women after Major Joint Arthroplasty in the Republic of Sakha (Yakutia)

The aim of this study was to assess the risk factors for thromboembolic complications after total arthroplasty of large joints in women in Yakutia conditions to optimize the management tactics of this category of patients. The average age of women was 59.98±11.56 years in the age range from 50 to 70 years. In order to validate the study, women were divided into 2 groups. The main group consisted of 284 women undergoing total knee arthroplasty (Group 1). The comparison group included 147 women undergoing total hip arthoplasty (Group 2). The study demonstrated that hypertension was more common in patients of Group 1 than in patients of Group 2. However, the incidence of coronary heart disease and heart rhythm disorder was detected most frequently in patients with total hip arthroplasty. Obesity, thrombosis of the veins of the lower extremities, and liver disease were detected with almost the same frequency in women with total knee arthroplasty and those with total hip arthroplasty. The frequency of occurrence of complications depending on the risk factors for thromboembolic complications and the type of surgical treatment of the joint was equal in the two groups of studied patients

Cadherins and cardiovascular disease

Cardiovascular diseases encompass an enormous range of conditions arising through an equally diverse aetiology. The cadherin superfamily of cell surface adhesion molecules have long been recognised for their crucial roles in morphogenesis and controlled growth and turnover in adult tissues. Thus, their involvement in the development of cardiovascular diseases characterised by tissue remodelling can be predicted. However, given the diversity of cadherins expressed on resident cells in cardiac and vascular tissue and their assorted and frequently overlapping functions that extend beyond mere mediation of adhesive interactions, definition of specific roles in the progression of cardiovascular diseases can be confounding. Compared with the fields of embryogenesis and oncology, investigations targeted specifically toward delineation of the participation of cadherins in cardiovascular disease are remarkably scant. In this article we offer the reader a brief introduction to members of the cadherin superfamily, and review the involvement of cadherins in cardiac diseases (dilated and dysplastic cardiomyopathies) and vascular diseases (atherosclerosis and restenosis) in which prominent alterations in tissue architecture occur and ultimately cause the clinical manifestations and complications of the diseases. Putative functions of the different cadherins expressed in cardiomyocytes, smooth muscle cells and endothelial cells are discussed

Remotely Self-Healable, Shapeable and pH-Sensitive Dual Cross-Linked Polysaccharide Hydrogels with Fast Response to Magnetic Field

The development of actuators with remote control is important for the construction of devices for soft robotics. The present paper describes a responsive hydrogel of nontoxic, biocompatible, and biodegradable polymer carboxymethyl hydroxypropyl guar with dynamic covalent cross-links and embedded cobalt ferrite nanoparticles. The nanoparticles significantly enhance the mechanical properties of the gel, acting as additional multifunctional non-covalent linkages between the polymer chains. High magnetization of the cobalt ferrite nanoparticles provides to the gel a strong responsiveness to the magnetic field, even at rather small content of nanoparticles. It is demonstrated that labile cross-links in the polymer matrix impart to the hydrogel the ability of self-healing and reshaping as well as a fast response to the magnetic field. In addition, the gel shows pronounced pH sensitivity due to pH-cleavable cross-links. The possibility to use the multiresponsive gel as a magnetic-field-triggered actuator is demonstrated