Vascular Disease Research Research Articles

Potential causal relationships between blood metabolites, inflammatory cytokines, and venous thromboembolism.

Venous thromboembolism (VTE) is the abnormal coagulation of blood in deep veins, which impairs venous return and includes deep vein thrombosis (DVT) and pulmonary embolism (PE). The incidence of VTE is increasing, leading to severe complications and sequelae. Despite the widespread application of multi-omics analyses in vascular disease research, identifying the specific links between various metabolic products, cytokines, and VTE, as well as their potential mediating roles, requires further validation due to confounding factors. Summary statistics for 1,091 metabolites, 309 metabolite ratios (8,299 individuals), and 41 inflammatory cytokines (8,293 individuals) were obtained from the largest genome-wide association studies (GWAS). Summary statistics for VTE (21,021 cases, 391,160 controls), DVT (6,501 cases, 357,111 controls), and PE (10,046 cases, 401,128 controls) were derived from the FinnGen R10 dataset. We initially examined causal relationships using two-sample MR analysis, followed by Two-step Mendelian Randomization (TSMR) and Multivariable Mendelian Randomization (MVMR) to identify potential mediating mechanisms. We identified causal associations for 78 blood metabolites with VTE, 79 with DVT, and 81 with PE. Among all 41 inflammatory cytokines included, only platelet-derived growth factor BB (PDGF-BB) levels showed a causal relationship with increased risks of VTE, DVT, and PE. MVMR analysis revealed that the associations between glycocholate levels and VTE, DVT, and PE were mediated by PDGF-BB, accounting for 14.54% (p=2.84E-04), 17.10% (p=3.64E-05), and 10.44% (p=1.39E-02), respectively. Furthermore, the associations between dodecanedioate (C12:1-DC) levels and VTE and DVT were also mediated by PDGF-BB, accounting for 12.79% (p=6.10E-04) and 12.17% (p=2.13E-04), respectively. This study reveals significant associations between specific blood metabolites and the risks of VTE, DVT, and PE, with some associations potentially mediated by PDGF-BB.

Alleviation of Angiotensin II-Induced Vascular Endothelial Cell Injury Through Long Non-coding RNA TUG1 Inhibition.

Hypertension damages endothelial cells, causing vascular remodelling. It is caused by Ang II-induced endothelial cell (EC) destruction. The long noncoding RNA (lncRNAs) are emerging regulators of endothelium homeostasis. Injured endothelium expresses lncRNA taurine-upregulated gene 1 (TUG1), which may mediate endothelial cell damage, proliferation, apoptosis, and autophagy and contribute to cardiovascular disease. However, uncertainty surrounds the function of lncRNA TUG1, on arterial endothelium cell damage. This research aimed to investigate the role and mechanism of lncRNA TUG1 in vascular endothelial cell injury. A microarray analysis of lncRNA human gene expression was used to identify differentially expressed lncRNAs in human umbilical vein endothelial cell (HUVEC) cultures. The viability, apoptosis, and migration of Ang II-treated HUVECs were then evaluated. In order to investigate the role of lncRNA TUG1 in hypertension, qRT-PCR, western blotting, and RNA-FISH were used to examine the expression of TUG1 in SHR mice. Ang II-activated HUVECs and SHR rats' abdominal aortas highly express the lncRNA TUG1. LncRNA TUG1 knockdown in HUVECs could increase cell viability, reduce apoptosis, and produce inflammatory factors. In SHR rat abdominal aortas, lncRNA TUG1 knockdown promoted proliferation and inhibited apoptosis. HE spotting showed that lncRNA TUG1 knockdown improved SHR rats' abdominal aorta shape. lncRNA TUG1 knockdown promotes miR-9- 5p, which inhibits CXCR4 following transcription. The lncRNA TUG1/miR-9-5p/CXCR4 axis and vascular cell injury were also examined. MiR-9-5p silencing or CXCR4 overexpression lowered cell survival, apoptosis, and lncRNA TUG1-induced IL-6 and NO expression. lncRNA TUG1 suppression could reduce Ang II-induced endothelial cell damage by regulating and targeting miR-9-5p to limit CXCR4 expression and open new vascular disease research pathways.

Revolutionizing vascular health through the temporal convolutional transformer for drug screening and model evolution

Vascular illnesses include a spectrum of disorders affecting the blood vessels and continue to be major global health challenges. Vascular disorders are major worldwide health concerns that require ongoing development of drug screening models in order to find efficient treatment approaches. The ever-changing field of vascular health demands novel ways to medication screening due to the enduring difficulties presented by a variety of illnesses. This abstract explores a paradigm shift, highlighting the innovative role of the Temporal Convolutional Transformer (TCT) in redefining drug screening techniques and promoting model evolution. With its seamless integration of transformer mechanisms and temporal convolutional layers, the TCT is a revolutionary hybrid algorithm. Because of this special combination, the model can simultaneously identify spatial subtleties and capture temporal dynamics in complicated biological information. The temporal convolutional layers of the TCT are particularly good at revealing the sequential dependencies that are present in the development of vascular disorders. The model ensures a detailed knowledge of the developing nature of these diseases by analyzing temporal dynamics with skill. Simultaneously, the TCT’s transformer mechanisms enable a thorough examination of long-range interdependence and global interconnections. The TCT’s dual capability establishes it as a comprehensive solution by offering a nuanced perspective on spatial patterns that are essential for identifying the complexity of vascular health. The TCT is hybrid in the sense that it can learn features at several scales, supporting different temporal and spatial resolutions. This flexibility guarantees that the model may extract pertinent information at various scales, enhancing the characterization of the complex nature of vascular illnesses. The TCT is positioned as a holistic solution since its transformer mechanisms allow for a thorough investigation of long-range dependencies and global interconnections at the same time. This combined capacity offers a sophisticated viewpoint on spatial patterns that is essential for understanding the intricacies of vascular health. Moreover, the remarkable flexibility of the TCT to dynamic temporal scales is consistent with the dynamic character of biological processes, providing a strong and adaptable framework for drug screening. The TCT is used in many different fields of vascular disease research. The model performs well in image-based screening, collecting sequential dependencies over time and processing spatial information from medical imaging datasets. The TCT’s capacity to identify long-range dependencies is essential for molecular interaction research since it helps to clarify the complex pathways associated with vascular disorders. Its adaptability also extends to personalized treatment approaches, which allow for the efficient modeling of patient-specific data, including genetic information. The TCT is a revolutionary tool that will continue to evolve as drug screening models do. By integrating temporal convolutional and transformer mechanisms, its all-encompassing methodology provides a sophisticated and comprehensive approach to deciphering the intricacies of vascular disorders. Across all evaluated metrics, the proposed method achieves near-perfect accuracy of 98.45%, sensitivity of 93.45%, specificity of 98.43%, precision of 84.25, AUC of 99 % and F1 score values 96.01%, respectively. This abstract sheds light on how the TCT has significantly changed drug development approaches, opening the door for more focused and effective therapies in the field of vascular health.

Porous boron-doped graphitic carbon nitride-based label-free electrochemical immunoassay of vascular endothelial cadherin.

As a main connecting protein between endothelial cells, vascular endothelial cadherin (CD144) is involved in regulating vascular remodeling and maintaining vascular integrity. It is regarded as a marker of endothelial dysfunction and injury. Quantitative determination of CD144 is of importance in pathology research, diagnosis and treatment of vascular diseases. A label-free electrochemical method for the immunoassay of CD144 was developed in this work. CD144 antibodies were assembled on a glassy carbon electrode modified with porous boron-doped carbon nitride (B-GCN) and gold nanoparticles (AuNPs) in the presence of protein A. The binding of CD144 on the antibody-modified electrode induced serious steric hindrance, inhibiting the diffusion of ferri-/ferrocyanide from the bulk electrolyte to the electrode interface. The change of the differential pulse voltammetric response displayed a linear relationship with the concentration of CD144 between 0.500 and 400 ng mL-1. The new electrochemical sensor showed some good performances including good selectivity, high stability and satisfactory reproducibility. The cellular morphology observation and activity measurement showed that the dysfunction of vascular endothelial cells appeared in the presence of high-content NaCl. The electrochemical analysis reveals a positive correlation between the release amount of CD144 from the dysfunctional cells and the NaCl concentration in the growth medium.

The impact of socioeconomic status on the burden of atherosclerosis, and the effect of intensive preventive therapy on its progression: A retrospective cohort study

Background and aimsSocioeconomic status (SES) is associated with cardiovascular disease. However, the relationship between SES and atherosclerosis is not well documented. This study aims to explore this relationship. MethodsThis is a retrospective cohort study in London, Ontario Canada. It includes 6,907 subjects from a vascular prevention centre at baseline, with long term follow up from 1989 to 2021 (total ultrasound examinations 27,103). Using carotid ultrasound, the burden of atherosclerosis was measured as total plaque area (TPA). The Ontario Marginalization Index (OMI) was used to identify SES of participants' neighborhoods. We used a Bayesian hierarchical regression and mixed effects model to identify associations between SES, baseline TPA and plaque progression. In 2003, we implemented more intensive therapy of vascular risk factors after 2003 (called “Treating arteries instead of risk treating factors”); therefore, we compared our findings before and after 2003. ResultsSES was found to have a significant association with TPA, with lower SES associated with higher TPA (adjusted odds ratio [OR] = 2.22, 95% Credible interval [CrI]: 1.37, 3.66). While we observed a higher rate of plaque progression with lower SES in those treated before 2003 (OR = 1.46, 95% CrI:1.04, 2.06), there was no significant association between plaque progression and SES after implementation more intensive therapy (OR = 0.99, 95% CrI: 0.78, 1.27). ConclusionsSES has a strong association with atherosclerosis and should be considered an important risk factor in clinical practice and vascular disease research. Intensive preventive therapy can prevent plaque progression irrespective of baseline SES.

Medical Image-Based Computational Fluid Dynamics and Fluid-Structure Interaction Analysis in Vascular Diseases.

Hemodynamic factors, induced by pulsatile blood flow, play a crucial role in vascular health and diseases, such as the initiation and progression of atherosclerosis. Computational fluid dynamics, finite element analysis, and fluid-structure interaction simulations have been widely used to quantify detailed hemodynamic forces based on vascular images commonly obtained from computed tomography angiography, magnetic resonance imaging, ultrasound, and optical coherence tomography. In this review, we focus on methods for obtaining accurate hemodynamic factors that regulate the structure and function of vascular endothelial and smooth muscle cells. We describe the multiple steps and recent advances in a typical patient-specific simulation pipeline, including medical imaging, image processing, spatial discretization to generate computational mesh, setting up boundary conditions and solver parameters, visualization and extraction of hemodynamic factors, and statistical analysis. These steps have not been standardized and thus have unavoidable uncertainties that should be thoroughly evaluated. We also discuss the recent development of combining patient-specific models with machine-learning methods to obtain hemodynamic factors faster and cheaper than conventional methods. These critical advances widen the use of biomechanical simulation tools in the research and potential personalized care of vascular diseases.

Identification of CD157-Positive Vascular Endothelial Stem Cells in Mouse Retinal and Choroidal Vessels: Fluorescence-Activated Cell Sorting Analysis.

PurposeCD157 (also known as Bst1) positive vascular endothelial stem cells (VESCs), which contribute to vascular regeneration, have been recently identified in mouse organs, including the retinas, brain, liver, lungs, heart, and skin. However, VESCs have not been identified in the choroid. The purpose of this study was to identify VESCs in choroidal vessels and to establish the protocol to isolate retinal and choroidal VESCs.MethodsWe established an efficient protocol to create single-cell suspensions from freshly isolated mouse retina and choroid by enzymatic digestion using dispase, collagenase, and type II collagenase. CD157-positive VESCs, defined as CD31+CD45−CD157+ cells, were sorted using fluorescence-activated cell sorting (FACS).ResultsIn mouse retina, among CD31+CD45− endothelial cells (ECs), 1.6 ± 0.2% were CD157-positive VESCs, based on FACS analysis. In mouse choroid, among CD31+CD45− ECs, 4.5 ± 0.4% were VESCs. The CD157-positive VESCs generated a higher number of EC networks compared with CD157-negative non-VESCs under vascular endothelial growth factor (VEGF) in vitro cultures. The EC network area, defined as the ratio of the CD31-positive area to the total area in each field, was 4.21 ± 0.39% (retinal VESCs) and 0.27 ± 0.12% (retinal non-VESCs), respectively (P < 0.01). The EC network area was 8.59 ± 0.78% (choroidal VESCs) and 0.14 ± 0.04% (choroidal non-VESCs), respectively (P < 0.01). The VESCs were located in large blood vessels but not in the capillaries.ConclusionsWe confirmed distinct populations of CD157-positive VESCs in both mouse retina and choroid. VESCs are located in large vessels and have the proliferative potential. The current results may open new avenues for the research and treatment of ocular vascular diseases.

Spatiotemporal absorption fluctuation imaging based on U-Net.

.SignificanceFull-field optical angiography is critical for vascular disease research and clinical diagnosis. Existing methods struggle to improve the temporal and spatial resolutions simultaneously.AimSpatiotemporal absorption fluctuation imaging (ST-AFI) is proposed to achieve dynamic blood flow imaging with high spatial and temporal resolutions.ApproachST-AFI is a dynamic optical angiography based on a low-coherence imaging system and U-Net. The system was used to acquire a series of dynamic red blood cell (RBC) signals and static background tissue signals, and U-Net is used to predict optical absorption properties and spatiotemporal fluctuation information. U-Net was generally used in two-dimensional blood flow segmentation as an image processing algorithm for biomedical imaging. In the proposed approach, the network simultaneously analyzes the spatial absorption coefficient differences and the temporal dynamic absorption fluctuation.ResultsThe spatial resolution of ST-AFI is up to , and the temporal resolution is up to 0.032 s. In vivo experiments on 2.5-day-old chicken embryos were conducted. The results demonstrate that intermittent RBCs flow in capillaries can be resolved, and the blood vessels without blood flow can be suppressed.ConclusionsUsing ST-AFI to achieve convolutional neural network (CNN)-based dynamic angiography is a novel approach that may be useful for several clinical applications. Owing to their strong feature extraction ability, CNNs exhibit the potential to be expanded to other blood flow imaging methods for the prediction of the spatiotemporal optical properties with improved temporal and spatial resolutions.

Epidemiology of Peripheral Vascular Disease in the Long Life Family Study (LLFS)

Atherosclerotic occlusion of peripheral arteries is a major contributor to morbidity and mortality in older adults. Our aim was to describe the epidemiology of peripheral artery disease (PAD) and other peripheral vascular disease (OPD) in the LLFS. 3248 individuals from 509 families (1182 probands, mean age 89; 2066 offspring, mean age 60) had doppler ankle-brachial index (ABI) assessment. Measures were performed twice for each posterior tibial artery and minimum of the mean ABI was used. PAD was defined as any ABI<0.9. OPD was defined as any ABI >1.4 or ≥1 non-compressible artery. Stepwise linear or logistic regression determined significant independent clinical and demographic predictors (P<0.05) after adjustment for age, sex, study center, and familial relatedness. Overall, ABI had a median of 1.2 with 7.4% PAD (18.1% probands, 1.2% offspring; P<0.001). OPD prevalence was 10.6% and was more common than PAD in offspring (8.1%). Age-adjusted OPD was higher in men (13.3%) than women (8.3%, P<0.001), while age-adjusted PAD did not did not differ by sex (P=0.45). Predictors of PAD included greater age and systolic blood pressure, lower diastolic blood pressure, prevalent kidney disease, antihypertensive use, and current smoking. Predictors of OPD included greater age, male sex, and current smoking. In these exceptionally long-lived families, PAD was low compared to other epidemiologic studies. However, OPD including non-compressible arteries, a marker of arterial stiffness, was more prevalent than PAD. These findings in long-lived families highlight a need for more epidemiologic research in other peripheral vascular disease in adults from the general population.

A Simple and Convenient Method to Isolate and Culture Rat Aorta Endothelial Cells

Aim: Endothelial injury results in vascular disorders. Culture of endothelial cells (ECs) is important to investigate the pathogenesis of vascular diseases. ECs of rat aorta are widely applied in these researches. However, there are many problems to isolate them, which make it hard to culture primary ECs. In the present study, we established a simple and convenient method to isolate and culture rat aorta ECs. Methods: Two 5ml centrifuge tubes were prepared. An opening (3 mm × 25 mm) was made in one tube wall while the other was cut in half longitudinally. After the rat aorta was dissected along one side and attached to the wall of the half tube, the tube with an opening and the half tube with aorta were mated and secured by a rotund metal clip. Then, ECs were digested via the opening by 0.2% collagenase I at 37℃ for 1 h and identified by immunofluorescence of von Willebrand factor (vWF) and smooth muscle actin (SMA). Results: A simple method for isolating ECs were established. Cultured ECs exhibited typical “cobblestone” morphology at confluence. vWF was positively expressed in the ECs, and neither the negative stain of vWF nor the positive stain of SMA was found. Conclusion: This simple and convenient method to isolate and culture ECs of rat aorta can be implemented with readily available 5ml centrifuge tubes and will greatly benefit the research of vascular diseases.

Reviewers for Diabetes and Vascular Disease Research: 2020

Reviewers for Diabetes and Vascular Disease Research: 2020

NIR-emitting semiconducting polymer nanoparticles for in vivo two-photon vascular imaging.

Two-photon fluorescence (TPF) imaging holds great promise for real-time monitoring of cerebral ischemia-reperfusion injury, which is important for the clinical diagnosis of stroke. However, biocompatible and photostable NIR-emitting probes for TPF imaging of ischemic stroke are lacking. Herein, we report the first NIR-emitting TPF probe (named NESPN) prepared using semiconducting polymers for TPF imaging of cerebral ischemia. By virtue of its excellent biocompatibility with the nervous system and bright fluorescence NIR emission, NESPN enables the real-time imaging of mouse brain vasculature with micrometer-scale spatial resolution, realizing clear visualization of ultrafine capillaries (∼3.16 μm). Moreover, NESPN can be utilized in the dynamic monitoring of cerebral blood flow velocity. Microangiography using NESPN was successfully used to indicate the openness of the penumbra area in the mouse brain stroke model. More importantly, this technique allows us to continuously monitor the whole process of ischemic stroke and subsequent reperfusion. This work provides a new and versatile tool for vascular research and diagnosis of vascular diseases.

Accessing the academic influence of vascular surgeons within the National Institutes of Health iCite database

ObjectiveA diverse array of measures are used to evaluate academic physicians. One critical factor is the scholarly influence an author has on the research discourse within a field. The National Institutes of Health recently developed the Relative Citation Ratio (RCR) as a method to quantify the influence of published research. The aim of this study was to examine the academic influence of vascular surgeons using RCR within common vascular disease research fields. MethodsUsing the PubMed and National Institutes of Health iCite databases, scientific fields of abdominal and thoracic aortic aneurysm, peripheral artery disease (PAD), cerebral vascular occlusive disease, deep venous thrombosis (DVT), and venous insufficiency were queried for the highest rated RCR articles in each category (2007-2012). To calculate the RCR, article citation rates are divided by an expected citation rate derived from performance of articles in the same field, with the resulting RCR being level and field independent. Article categories were divided into basic science, health services, and clinical research on the basis of two independent reviews. For articles, academic backgrounds of the first, second, and last authors (“influential authors”) were collected analyzing procedural specialty: surgery, medicine subspecialty (cardiology, neurology, nephrology), radiology/engineering, and other (anesthesia and pediatrics). Statistical significance between scientific fields and academic background was determined using Student t-test or analysis of variance followed by Newman-Keuls post hoc test. ResultsThe academic influence of vascular surgeons varied substantially by the scientific field. Vascular surgeons compared with medical specialists were found to have the highest academic influence in abdominal aortic aneurysm research, composing 51% of the influential authors on the highest rated RCR studies (5.9 ± 0.8 vs 5.6 ± 0.8; P = .6). In contrast, vascular surgeons composed only 13% of influential authors compared with medical specialists in DVT (RCR, 2.6 ± 0.3 vs 15.7 ± 1.7; P < .003) and 18% in PAD (RCR, 1.9 ± 0.5 vs 2.1 ± 0.2; P = .78) research fields. Grouping all vascular fields of study together, no difference in RCR was found between vascular surgery and radiology/engineering. However, the mean RCR was significantly lower for vascular surgeons compared with medical subspecialties (4.5 ± 0.4 vs 6.8 ± 0.5; P < .05). ConclusionsVascular surgeons exhibit a moderate academic influence in the field of aneurysmal disease but lag behind medical subspecialists in high-impact scientific contributions to the fields of PAD and DVT. Innovative strategies and collaborations are likely needed to increase the influence of vascular surgeons on the academic discourse of several vascular disease research fields.

Standardized and Scalable Assay to Study Perfused 3D Angiogenic Sprouting of iPSC-derived Endothelial Cells In Vitro.

Pre-clinical drug research of vascular diseases requires in vitro models of vasculature that are amendable to high-throughput screening. However, current in vitro screening models that have sufficient throughput only have limited physiological relevance, which hinders the translation of findings from in vitro to in vivo. On the other hand, microfluidic cell culture platforms have shown unparalleled physiological relevancy in vitro, but often lack the required throughput, scalability and standardization. We demonstrate a robust platform to study angiogenesis of endothelial cells derived from human induced pluripotent stem cells (iPSC-ECs) in a physiological relevant cellular microenvironment, including perfusion and gradients. The iPSC-ECs are cultured as 40 perfused 3D microvessels against a patterned collagen-1 scaffold. Upon the application of a gradient of angiogenic factors, important hallmarks of angiogenesis can be studied, including the differentiation into tip- and stalk cell and the formation of perfusable lumen. Perfusion with fluorescent tracer dyes enables the study of permeability during and after anastomosis of the angiogenic sprouts. In conclusion, this method shows the feasibility of iPSC-derived ECs in a standardized and scalable 3D angiogenic assay that combines physiological relevant culture conditions in a platform that has the required robustness and scalability to be integrated within the drug screening infrastructure.

Reviewers for Diabetes and Vascular Disease Research: 2018

Reviewers for Diabetes and Vascular Disease Research: 2018

Translational research in retinal vascular disease. An approach.

The clinical presentation of the most frequent vision threatening retinal diseases is dominated by lesions indicating that disturbances in retinal blood flow are involved in the pathogenesis of these diseases. The present review describes the experience from a translational strategy pursued to investigate retinal vascular diseases with diabetic retinopathy as the main object. The normal regulation of retinal blood flow is investigated in porcine retinal vessels invitro and exvivo. Subsequently, the invitro findings are translated to clinical studies in normal persons invivo, and it is investigated whether the mechanisms are disturbed in retinal vascular disease. This is followed by clinical intervention studies on these diseases. The approach has been used to investigate pressure autoregulation, metabolic autoregulation and vasomotion in retinal vessels. The investigations have shown that retinal vascular tone can be regulated by receptor-specific agonists and antagonists to vasoactive compounds such as purines, prostaglandins and nitric oxide synthesis and that the vasoactive effects can be modulated by the concentration and the mode of administration of these compounds. Additionally, it has been shown that retinal precapillary arterioles and capillaries not visible by ophthalmoscopy may play an important role for the pathophysiology of retinal vascular disease and its treatment. Future studies should focus on investigating normal and pathological regulation of retinal blood flow in these smaller vessels.

Localized Intra-Arterial Gene Delivery Using AAV.

In vivo gene therapy is a tremendous tool for a wide variety of genetic modifications. However, often a specific and precise local administration of the viral vector is necessary to deliver the genetic payload in vivo. For many animal studies using viral vectors, such as those investigating neurological disorders, the vector is targeted directly into the tissue/organ of interest. On the other hand, in vascular disease research, viral vectors are administered systemically, either via a tail vein injection or through catheter-mediated infusion, which results in off-target transduction of cells and tissues. Targeting cells in the vascular wall without off-target activity, however, requires localized delivery in order to efficiently target cells of the internal vasculature. Here we describe a novel murine in vivo targeted intra-arterial viral vector delivery method, which has been developed in order to be able to perform more intricate studies in cardiovascular disease.

3D human microvessel-on-a-chip model for studying monocyte-to-endothelium adhesion under flow - application in systems toxicology.

Lifestyle and genetic factors can lead to the development of atherosclerosis and, ultimately, cardiovascular adverse events. Rodent models are commonly used to investigate mechanism(s) of atherogenesis. However, the 3Rs principles, aiming to limit animal testing, encourage the scientific community to develop new physiologically relevant in vitro alternatives. Leveraging the 96-chip OrganoPlate®, a microfluidic platform, we have established a three-dimensional (3D) model of endothelial microvessels-on-a-chip under flow using primary human coronary arterial endothelial cells. As functional readout, we have set up an assay to measure the adhesion of monocytes to the lumen of perfused microvessels. For monitoring molecular changes in microvessels, we have established the staining and quantification of specific protein markers of inflammation and oxidative stress using high content imaging, as well as analyzed transcriptome changes using microarrays. To demonstrate its usefulness in systems toxicology, we leveraged our 3D vasculature-on-a-chip model to assess the impact of the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product, and the 3R4F reference cigarette on the adhesion of monocytic cells to endothelial microvessels. Our results show that THS 2.2 aerosol-conditioned medium had a reduced effect on monocyte-endothelium adhesion compared with 3R4F smoke-conditioned medium. In conclusion, we have established a relevant 3D vasculature-on-a-chip model for investigating leukocyte-endothelial microvessel adhesion. A case study illustrates how the model can be used for product testing in the context of systems toxicology-based risk assessment. The current model and its potential further development options also open perspectives of applications in vascular disease research and drug discovery.

PTGIS is a Novel Susceptibility Gene for Pulmonary Arterial Hypertension

Background: Genetic variants such as inactivating mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene account for approximately 15-20% of the etiology of idiopathic pulmonary arterial hypertension (IPAH). Increasing evidence indicates the existence of other IPAH susceptibility genes. Methods: The whole-genome sequencing was performed in a discovery cohort including 42 IPAH patients who are lacking BMPR2 mutations. Putative IPAH genes were validated in an independent cohort that included 188 IPAH patients and 968 healthy controls. Functional assessments were conducted to analyze the effects of candidate genetic variants on transcript splicing, enzymatic activity and function. Results: An enrichment of rare variants in the gene encoding prostacyclin synthase (PTGIS) was initially identified by the whole-genome sequencing. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In total, fourteen patients (6.1%) were heterozygous for three PTGIS rare variants, including one splice-site variant (c.521 1G>A) and two missense variants (R252Q, A447T). These rare variants conferred a 7.8-fold greater risk of IPAH (95% confidence interval (CI), 3.2 to 18.8; P=5 x 10-6). Inhaled iloprost induced more significantly decrease of pulmonary vascular resistance (P=0.001) and increase of cardiac index (P A variant resulted in aberrant mRNA transcripts. The functional studies showed that the two missense variants caused a decrease in prostacyclin production and increased cell death in pulmonary microvascular endothelial cells. Conclusions: We have identified three loss-of-function rare variants in the PTGIS gene from two independent IPAH cohorts. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation and cause deleterious effects. These results provide a novel finding that PTGIS rare variants are involved in the pathogenesis of IPAH. Funding: The work was supported by the following grants: the Beijing Natural Science Foundation (7181009, 7172180), the National Natural Science Foundation of China (81320108005), the National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002, 2016-I2M-4-003), the National Key Research and Development Program of China (2016YFC0901502), Sanming Project of Medicine in Shenzhen-Professor Zhi-Cheng Jing's Group for Precise Medicine Research in Thrombosis and Vascular Disease (SZSM201502001) , and the fund from State Key Laboratory of Cardiovascular Disease (2016-kf04, 2018ZR-02). Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: The study protocol was approved by the ethics committees of Shanghai Pulmonary Hospital and FuWai Hospital. The participants, who were all of Chinese Han ancestry, provided written informed consent.

Current status in the field of vascular surgery in the era of innovation and scientific technology

Vascular surgery largely benefits from the innovation foundation of the 19th century surgical flight development period. Now, a new round of science and technology and industrial revolution promote the development of vascular surgery. The key areas related to vascular surgery medical innovation, including individualized treatment, new materials, biological medicine, high-performance medical apparatus and instruments, and the field of artificial intelligence research make quick progress, which provides support for the development of the discipline. In general, the development of vascular surgery is still growing and improving. With the progress of population aging, the incidence of diseases required for vascular surgery is increasing year by year. The rapid development of imaging technology has greatly increased the detection rate of diseases required for vascular surgery and promoted the vigorous development of intracavitary technology. And the innovation technology and informatization provide the opportunity and challenge for the research of vascular surgery diseases. Understanding new technology and new information has a great impact on the development of this profession. Regardless of medical research, the ultimate goal is to serve the health of mankind. Key words: Vascular surgery; Innovation; Disease; Treatment