Endothelial Vascular Cell Adhesion Research Articles

Cadherin-5 facilitated the differentiation of human induced pluripotent stem cells into sinoatrial node-like pacemaker cells by regulating β-catenin.

Our study was conducted to investigate whether cadherin-5 (CDH5),a vascular endothelial cell adhesion glycoprotein, could facilitate the differentiation of human induced pluripotent stem cells (hiPSCs)into sinoatrial node-like pacemaker cells (SANLPCs),following previous findings of silk-fibroin hydrogel-induced direct conversion of quiescent cardiomyocytes into pacemaker cells in rats through the activation of CDH5. In this study, the differentiating hiPSCs were treated with CDH5 (40 ng/mL) between Day 5 and 7 during cardiomyocytes differentiation. The findings in the present study demonstrated that CDH5 stimulated the expression of pacemaker-specific markers while suppressing markers associated with working cardiomyocytes, resulting in an increased proportion of SANLPCs among hiPSCs-derived cardiomyocytes (hiPSC-CMs)population. Moreover, CDH5 induced typical electrophysiological characteristics resembling cardiac pacemaker cells in hiPSC-CMs.Further mechanistic investigations revealed that the enriched differentiation of hiPSCs into SANLPCs induced by CDH5 was partially reversed by iCRT14, an inhibitor of β-catenin. Therefore, based on the aforementioned findings, it could be inferred that the regulation of β-catenin by CDH5 played a crucial role in promoting the enriched differentiation of hiPSCs into SANLPCs, which presents a novel avenue for the construction of biological pacemakers in forthcoming research.

Fucoidan/collagen composite coating on magnesium alloy for better corrosion resistance and pro-endothelialization potential

Magnesium alloy stents (MAS) have broad application prospects in the treatment of cardiovascular diseases. However, poor corrosion resistance and biocompatibility greatly limit the clinical application of MAS. In this work, the coating consisting of MgF2 layer, polydopamine layer, fucoidan and collagen IV was constructed on Mg-Zn-Y-Nd (ZE21B) alloy to improve its corrosion resistance and pro-endothelialization potential. The fucoidan and collagen IV in the coating could obviously enhance the hemocompatibility and pro-endothelialization potential respectively. Compared with bare ZE21B alloy, the fucoidan/collagen composite coating modified ZE21B alloy possessed lower corrosion current density and better corrosion resistance. Moreover, the modified ZE21B alloy exhibited relatively low hemolysis rate, fibrinogen adsorption and platelet adhesion in the blood experiments, suggesting the improved hemocompatibility. Furthermore, the modified ZE21B alloy favorably supported the adhesion and proliferation of vascular endothelial cells (ECs) and effectively regulated the phenotype of smooth muscle cells (SMCs), thus improving the pro-endothelialization potential of vascular stent materials. The fucoidan/collagen composite coating can significantly improve the corrosion resistance and pro-endothelialization potential of ZE21B alloy, showing great potential in the development of degradable MAS.

Sacubitril/valsartan attenuates myocardial inflammation, hypertrophy, and fibrosis in rats with heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3β (GSK-3β) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-β1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF.

Technique for reducing the surgical porosity of small-diameter vascular grafts

High surgical porosity (SP) is one of the causes of significant blood loss, as well as hematoma formation. So, reducing the SP of small-diameter vascular grafts (VGs) is a crucial task.The objective of this work was to develop a technology for the formation of polycaprolactone (PCL)-based small-diameter VGs with a bioactive coating with reduced SP.Materials and methods. Porous VGs with an inner diameter of 3 mm were fabricated by electrospinning from 5% PCL solution with addition of 5–30% gelatin (PCL/G) on an NANON-01A unit (MECC CO, Japan). Bioactive coating was applied by sequential incubation of VGs in solutions of bovine serum albumin, heparin and platelet lysate with fixation in a glutaric aldehyde solution. The surface structure and mechanical properties of the samples were investigated. Functional properties of the bioactive VGs were evaluated in relation to their interaction with cell cultures in vitro.Results. It was found that introduction of gelatin into the working solution reduces SP from 30.4 ± 1.5 mL/(cm2 ·min) to 2.8 ± 0.5 ml/(cm2 ·min). It was shown that at a PCL/gelatin ratio of 9 : 1, the outer and inner sides of the bioactive VGs samples are characterized by surface uniformity (no defects), mechanical properties close to blood vessels of the same diameter (Young’s modulus 6.7 ± 2.1 MPa, tensile strength 26.7 ± 4.9 N and elongation to break 423 ± 80%) and ability to support adhesion and proliferation of human umbilical vein endothelial cell line, EA.hy926.Conclusion. Introduction of 10% gelatin content (by the polymer weight) into PCL solution reduces the SP of small-diameter VGs, leads to uniformity in their inner and outer surface, improvement in their mechanical properties without reducing their ability to support adhesion and proliferation of vascular endothelial cells.

A rat model of metabolic syndrome-related heart failure with preserved ejection fraction phenotype: pathological alterations and possible molecular mechanisms.

Heart failure with preserved ejection fraction (HFpEF) represents a syndrome involving multiple pathophysiologic disorders and clinical phenotypes. This complexity makes it challenging to develop a comprehensive preclinical model, which presents an obstacle to elucidating disease mechanisms and developing new drugs. Metabolic syndrome (MetS) is a major phenotype of HFpEF. Thus, we produced a rat model of the MetS-related HFpEF phenotype and explored the molecular mechanisms underpinning the observed pathological changes. A rat model of the MetS-related HFpEF phenotype was created by feeding spontaneously hypertensive rats a high-fat-salt-sugar diet and administering streptozotocin solution intraperitoneally. Subsequently, pathological changes in the rat heart and their possible molecular mechanisms were explored. The HFpEF rats demonstrated primary features of MetS, such as hypertension, hyperglycemia, hyperlipidemia, insulin resistance, and cardiac anomalies, such as left ventricular (LV) remodeling and diastolic impairment, and left atrial dilation. Additionally, inflammation, myocardial hypertrophy, and fibrosis were observed in LV myocardial tissue, which may be associated with diverse cellular and molecular signaling cascades. First, the inflammatory response might be related to the overexpression of inflammatory regulators (growth differentiation factor 15 (GDF-15), intercellular adhesion molecule-1 (ICAM-1), and vascular endothelial cell adhesion molecule-1 (VCAM-1)). Secondly, phosphorylated glycogen synthase kinase 3β (GSK-3β) may stimulate cardiac hypertrophy, which was regulated by activated -RAC-alpha serine/threonine-protein kinase (AKT). Finally, the transforming growth factor-β1 (TGF-β1)/Smads pathway might regulate collagen production and fibroblast activation, promoting myocardial fibrosis. The HFpEF rat replicates the pathology and clinical presentation of human HFpEF with MetS and may be a reliable preclinical model that helps elucidate HFpEF pathogenesis and develop effective treatment strategies.

Integration of network pharmacology and proteomics to elucidate the mechanism and targets of traditional Chinese medicine Biyuan Tongqiao granule against allergic rhinitis in an ovalbumin-induced mice model

Ethnopharmacological relevanceBiyuan Tongqiao granule (BYTQ) is a traditional Chinese medicine that has been used in China to clinically treat patients with allergic rhinitis (AR), yet its underlying mechanism and targets remains unclear. Aim of the studyThe study aimed to investigate the potential mechanism of BYTQ against AR using the ovalbumin (OVA) -induced AR mice model. Integrating network pharmacology and proteomics to investigate possible targets of BYTQ for AR. Materials and methodsThe compounds in BYTQ were analyzed using UHPLC-ESI-QE-Orbitrap-MS. The OVA/Al(OH)3 were used to induce the AR mice model. The nasal symptoms, histopathology, immune subsets, inflammatory factors, and differentially expressed proteins were examined. Proteomics analysis elucidated the potential mechanisms of BYTQ to improve AR, which was further validated by Western blot (WB) assay. The compounds and potential targets of BYTQ were systematically elucidated by integrating network pharmacology and proteomics analysis to explore the mechanism. The binding affinity between key potential targets and corresponding compounds was then validated using molecular docking. Molecular docking results were verified by a western blotting and cellular thermal shift assay (CETSA). ResultsA total of 58 compounds were identified from BYTQ. BYTQ significantly suppressed AR symptoms by inhibiting the release of OVA-specific immunoglobulin E (IgE) and histamine, improving the pathological injury of nasal mucosal tissue, and regulating the proportions of lymphocytes to maintain immune balance. Proteomics analysis showed that the cell adhesion factors and focal adhesion pathway might be potential mechanism of BYTQ against AR. The levels of E-selectin, vascular endothelial cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) proteins in the nasal mucosal tissue were significantly downregulated in the BYTQ-H group compared to the AR group. Integrating network pharmacology and proteomics analysis identified that SRC, PIK3R1, HSP90AA1, GRB2, AKT1, MAPK3, MAPK1, TP53, PIK3CA, and STAT3 may be potential protein targets for BYTQ to treat AR. Molecular docking analysis indicated that the active compounds of BYTQ could bind tightly to these key targets. In addition, BYTQ could inhibit OVA-induced phosphorylation levels of PI3K, AKT1, STAT3 and ERK1/2. The CETSA data suggested that BYTQ could improve the heat stability of PI3K, AKT1, STAT3 and ERK1/2. ConclusionsBYTQ suppresses E-selectin and VCAM-1 and ICAM1 expression by regulating PI3K/AKT and STAT3/MAPK signaling pathways, thus alleviating inflammation in AR mice. BYTQ is the aggressive treatment for AR.

Biodegradable Mg alloy modified with bioactive exosomes for cardiovascular stent application

Cardiovascular stent has been widely applied to treat cardiovascular disease (CVD), which is the major disease contribution to mortality in the world wide. Biodegradable magnesium (Mg) alloys are the encouraging materials in cardiovascular stents benefit from absorbability and biocompatibility. While, the ability of degradation is a double-edged sword for manufacture stent, modifying the surface to decrease the excessive degradation rate and promote the surface endothelialization could expand the prospect of the further application. In this work, the biodegradable Mg-Zn-Y-Nd alloy was modified by MgF2 and dopamine polymer film (PDA) as the corrosion resistance layer and the bonding layer respectively, and then the exosome, a natural nanoparticle contains mRNAs and proteins, was tailored to give the surface better biocompatibility. The electrochemical test and weight loss test reflected the MgF2-PDA/exosome coating increase the corrosion resistance of the Mg-Zn-Y-Nd alloy. The cytocompatibility data indicated the novel MgF2-PDA/exosome coating selectively reduced the tumor necrosis factor (TNF-α) expression and ROS release from macrophage, and promoted the α-SMA expression of smooth muscle cells. In addition, the MgF2-PDA/exosome coating also improved the adhesion, proliferation, CD31 expression and nitric oxide (NO) release of vascular endothelial cells (ECs), all of which contribute to the surface endothelialization. And the mechanism experiments showed the exosome released from the coating uptake by the ECs and assemble around the lysosome and mitochondria, and the released rate of the exosome on the coating is around 5 to7 days, indicating excellent multi-functions of MgF2-PDA/exosome coating in cardiovascular stent.

Luminal Surface Plasma Treatment of Closed Cylindrical Microchannels: A Tool toward the Creation of On-Chip Vascular Endothelium.

On-chip vascular microfluidic models provide a great tool to study aspects of cardiovascular diseases in vitro. To produce such models, polydimethylsiloxane (PDMS) has been the most widely used material. For biological applications, its hydrophobic surface has to be modified. The major approach has been plasma-based surface oxidation, which has been very challenging in the case of channels enclosed within a microfluidic chip. The preparation of the chip combined a 3D-printed mold with soft lithography and commonly available materials. We have introduced the high-frequency low-pressure air-plasma surface modification of seamless channels enclosed within a PDMS microfluidic chip. The plasma treatment modified the luminal surface more uniformly than in previous works. Such a setup enabled a higher degree of design freedom and a possibility of rapid prototyping. Further, plasma treatment in combination with collagen IV coating created a biomimetic surface for efficient adhesion of vascular endothelial cells as well as promoted long-term cell culture stability under flow. The cells within the channels were highly viable and showed physiological behavior, confirming the benefit of the presented surface modification.

MP46-07 PROGNOSTIC VALUE OF PREOPERATIVE VASCULAR ENDOTHELIAL GROWTH FACTOR AND VASCULAR CELL ADHESION MOLECULE-1 IN BLADDER CARCINOMA TREATED WITH RADICAL CYSTECTOMY

You have accessJournal of UrologyCME1 Apr 2023MP46-07 PROGNOSTIC VALUE OF PREOPERATIVE VASCULAR ENDOTHELIAL GROWTH FACTOR AND VASCULAR CELL ADHESION MOLECULE-1 IN BLADDER CARCINOMA TREATED WITH RADICAL CYSTECTOMY Keiichiro Mori, Victor Schuettfort, Takafumi Yanagisawa, Satoshi Katayama, Ekaterina Laukhtina, Benjamin Pradere, Pawel Rajwa, Hadi Mostafaei, Takahiro Kimura, and Shahrokh Shariat Keiichiro MoriKeiichiro Mori More articles by this author , Victor SchuettfortVictor Schuettfort More articles by this author , Takafumi YanagisawaTakafumi Yanagisawa More articles by this author , Satoshi KatayamaSatoshi Katayama More articles by this author , Ekaterina LaukhtinaEkaterina Laukhtina More articles by this author , Benjamin PradereBenjamin Pradere More articles by this author , Pawel RajwaPawel Rajwa More articles by this author , Hadi MostafaeiHadi Mostafaei More articles by this author , Takahiro KimuraTakahiro Kimura More articles by this author , and Shahrokh ShariatShahrokh Shariat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003292.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Identification of preoperative biomarkers capturing each tumor's biological and clinical potential is crucial to improve risk stratification in patients with urothelial carcinoma of the bladder (UCB). Angiogenesis-related marker vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1) have been shown to be elevated in UCB, but its predictive/prognostic role has not been determined. Thus, we aimed to investigate the predictive/prognostic value of these biomarkers in patients with UCB. METHODS: We enrolled 1,036 patients with clinically non-metastatic advanced UCB who underwent RC. The preoperative plasma levels of VEGF and VCAM-1 were measured. The correlation between plasma VEGF/VCAM-1 and pathological and survival outcomes was assessed. The clinical net benefit was evaluated using decision-curve analysis (DCA). RESULTS: Preoperative VCAM-1 was significantly elevated in patients with adverse pathological features. Higher VCAM-1 levels were independently associated with increased risk of lymph-node metastasis (LNM), ≥pT3 disease, and nonorgan-confined disease (NOCD; all p<0.001). Preoperative plasma VEGF/VCAM-1 were independently associated with recurrence-free, cancer specific, and overall survival (RFS/CSS/OS) in pre and postoperative multivariable models. Adding VCAM-1 to these models improved the discriminatory ability to predict all outcomes by a significant margin. On DCA, VCAM-1 addition to the reference models for LNM, NOCD, RFS, and CSS prediction resulted in relevant improvement. CONCLUSIONS: Elevated plasma VCAM-1 was associated with biologically and clinically aggressive UCB disease features. After validation, preoperative VCAM-1 may serve as biomarker to help identify patients likely to benefit from intensified/multimodal therapy. VCAM-1 also improved the discriminatory power of predictive/prognostic models and can be used to refine personalized clinical decision-making. Source of Funding: No funding © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e633 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Keiichiro Mori More articles by this author Victor Schuettfort More articles by this author Takafumi Yanagisawa More articles by this author Satoshi Katayama More articles by this author Ekaterina Laukhtina More articles by this author Benjamin Pradere More articles by this author Pawel Rajwa More articles by this author Hadi Mostafaei More articles by this author Takahiro Kimura More articles by this author Shahrokh Shariat More articles by this author Expand All Advertisement PDF downloadLoading ...

Cross-linking porcine peritoneum by oxidized konjac glucomannan: a novel method to improve the properties of cardiovascular substitute material

The use of natural polysaccharide crosslinkers for decellularized matrices is an effective approach to prepare cardiovascular substitute materials. In this research, NaIO4 was applied to oxidize konjac glucomannan to prepare the polysaccharide crosslinker oxidized konjac glucomannan (OKGM). The as-prepared crosslinker was then used to stabilize collagen-rich decellularized porcine peritoneum (DPP) to construct a cardiovascular substitute material (OKGM-fixed DPP). The results demonstrated that compared with GA-fixed DPP and GNP-fixed DPP, 3.75% OKGM [1:1.5 (KGM: NaIO4)]-fixed DPP demonstrated suitable mechanical properties, as well as good hemocompatibility, excellent anti-calcification capability, and anti-enzymolysis in vitro. Furthermore, 3.75% OKGM [1:1.5 (KGM: NaIO4)]-fixed DPP was suitable for vascular endothelial cell adhesion and rapid proliferation, and a single layer of endothelial cells was formed on the fifth day of culture. The in vivo experimental results also showed excellent histocompatibility. The current results demonstrted that OKGM was a novel polysaccharide cross-linking reagent for crosslinking natural tissues featured with rich collagen content, and 3.75% OKGM [1:1.5 (KGM: NaIO4)]-fixed DPP was a potential cardiovascular substitute material.Graphical

Prognostic value of angiogenesis related marker vascular endothelial growth factor and vascular cell adhesion molecule-1 in bladder carcinoma treated with radical cystectomy

Prognostic value of angiogenesis related marker vascular endothelial growth factor and vascular cell adhesion molecule-1 in bladder carcinoma treated with radical cystectomy

Evaluation of mechanical properties and biocompatibility of three-layer PCL/PLLA small-diameter vascular graft with pore diameter gradient

A three-layer small-diameter vascular graft (SDVG) of polycaprolactone (PCL) and l-polylactic acid (PLLA) with pore diameter gradient was prepared through combining variable-extrusion speed iterative electrospinning and ultrasonic reaming. The SEM results showed that the three-layer PCL/PLLA SDVG has distinct pore diameter gradient. The Young’s modulus, ultimate tensile strength (UTS), burst pressure (BP) and compliance of the vascular graft were high as 20.116 ± 0.465 MPa, 2.259 ± 0.141 MPa, 2050 ± 249 mmHg and 4.203 ± 0.330 %/100 mmHg, respectively. The UTS of the graft is similar to human coronary arteries. The BP meets the basic requirements to prevent aneurysmal dilation, and the compliance is higher than that of sheep carotid artery. The fluid–solid coupling simulation results showed that the graft had high mechanical properties to withstand the same blood flow velocity as human coronary arteries, and there was no stress concentration in the wall. Besides, it had good biocompatibility, promoting the adhesion and proliferation of rat vascular endothelial cells (ECs). The successful preparation of the small-diameter vascular graft with high mechanical properties for preventing itself from rupturing and ensuring the overall function, provides more possibilities for the clinical transplantation of small-diameter vascular grafts.

Strontium doped electrospinning fiber membrane with antibacterial and osteogenic properties prepared by pulse electrochemical method

• Composite fibers were prepared by electrostatic spinning and pulse electrochemical deposition. • PPy controls the slow release of Sr 2+ and Cu 2+ for a long time. • Good physiological stability and long-term antibacterial effect. • Fiber has good osteogenic and angiogenic properties. The osteogenic differentiation and new bone formation are commonly delayed by bacterial infection of orthopedic implants, which is urgent to be resolved quickly in the clinic. The current paper prepared a strontium-doped electrospinning fiber membrane with antibacterial and osteogenic properties by pulse electrochemical method. Polylactic acid/hydroxyapatite (PLLA/HA) composite fiber substrate was fabricated by electrospinning technology, and strontium doped SrHA/Cu/Polypyrrole (PPy) composite coating was constructed with pulse electrodeposition method on its surface. The strontium doping technique, degradation of Sr 2+ and Cu 2+ , cellular compatibility, and the antibacterial activity of the fiber membrane were examined. The results revealed that the deposition of phosphorus and calcium on composite fiber was the highest, indicating good biological activity. The release of Sr 2+ and Cu 2+ was stable and gradual due to the modulation of PPy. The composite fiber presented excellent antibacterial performance and the antibacterial rate was close to 100% against Staphylococcus aureus and Escherichia coli. Furthermore, it is conducive to the adhesion, spread, and proliferation of vascular endothelial cells and osteoblasts, namely outstanding osteogenesis and angiogenesis abilities. In conclusion, the multifunctional PLLA/HA@SrHA/Cu/PPy composite fiber membrane with good antibacterial and osteogenic activity by electrospinning technology and pulsed electrochemical deposition method provides an effective strategy for the poor bone healing of infected bone defects. Strontium doped antibacterial osteogenic PLLA/HA@SrHA/Cu/PPy composite fiber was constructed by electrostatic spinning and pulsed electrochemical deposition technology, which showed good antibacterial properties and had the ability to promote bone induction and angiogenesis.

P152 - Prognostic value of vascular endothelial growth factor and vascular cell adhesion molecule-1 in bladder carcinoma

P152 - Prognostic value of vascular endothelial growth factor and vascular cell adhesion molecule-1 in bladder carcinoma

Lack of NPR1 Increases Vascular Endothelial Adhesion through Induction of Integrin Beta 4.

Natriuretic peptide receptor 1 (NPR1) serves as a modulator of vascular endothelial homeostasis. Interactions between monocytes and endothelial cells may initiate endothelium dysfunction, which is known as an early hallmark of atherosclerosis. In this study, we performed RNA-sequencing analysis for the aorta of Npr1 knockout (Npr1+/−) mice and found that differentially expressed genes were significantly related to cell adhesion. This result was supported by an increased expression of intercellular adhesion molecule 1 (ICAM-1) in the aortic endothelium of Npr1+/− mice. Moreover, we observed that the knockdown of NPR1 increased ICAM-1 expression and promoted THP-1 monocyte adhesion to human umbilical vein endothelial cells (HUVECs). NPR1 overexpression decreased ICAM-1 expression and inhibited the adhesion of monocytes to HUVECs treated by TNF-α (a cell adhesion inducer). Further analysis showed that adhesion-related genes were enriched in the focal adhesion signaling pathway, in which integrin beta 4 (Itgb4) was determined as a key gene. Notably, ITGB4 expression increased in vascular endothelium of Npr1+/− mice and in NPR1-knockdown HUVECs. The deficiency of ITGB4 decreased ICAM-1 expression and attenuated monocyte adhesion to NPR1-knockdown endothelial cells. Additionally, a reduced NPR1 and an increased ITGB4 expression level were found in an atherosclerosis mouse model. In conclusion, our findings demonstrate that NPR1 deficiency increases vascular endothelial cell adhesion by stimulating ITGB4 expression, which may contribute to the development of atherosclerosis.

Avenanthramide-C Activates Nrf2/ARE Pathway and Inhibiting Ferroptosis Pathway to Improve Cognitive Dysfunction in Aging Rats.

Postoperative neurocognitive impairment (POCD) is a common complication after surgery and anesthesia, especially in elderly patients. Avenanthramide-C (AVC) test is a vascular endothelial cell adhesion molecule inhibitor with strong anti-inflammatory and antioxidant effects. The aim of this study was to investigate the effect and mechanism of AVC on POCD in aged rats to clarify the effect of AVC on POCD in aged rats. The aging rat model was established by continuous 200mg/kg propofol anesthesia. Repeated propofol anesthesia could severely impair spatial learning ability, memory and cognitive function, and could promote hippocampal apoptosis, oxidative stress injury, neuroinflammation and ferroptosis in aging rats. In addition, AVC not only improved cognitive dysfunction, but also significantly inhibited apoptosis, neuroinflammatory response, ferroptosis and oxidative stress level in the hippocampus of aging rats induced by repeated anesthesia. Further mechanistic studies manifested that the above protective effects of AVC on aging rats induced by repeated propofol anesthesia may be achieved by activating Nrf2/ARE pathway activity. AVC pretreatment has a preventive effect on cognitive dysfunction induced by repeated propofol anesthesia in aging rats, and the preventive effect of AVC may be realized by activating the Nrf2/ARE signaling pathway activity. Our results demonstrate that AVC preconditioning reduces postoperative neuronal loss and neuroinflammation, activates the Nrf2/ARE pathway, reduces oxidative stress injury, and improves POCD in aged rats.

STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion.

Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1β, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.

MiR-1290 promotes IL-8-mediated vascular endothelial cell adhesion by targeting GSK-3β.

MicroRNA-1290 (miR-1290) has been reported to be involved in many diseases and play a key role during the development process. However, the role of miR-1290 in atherosclerosis (AS) is still unclear. The current study showed that the expressions of miR-1290 were high in serum of patients with hyperlipidemia. The functional role of miR-1290 were then investigated in human umbilical vein endothelial cells (HUVECs). Here, we found that miR-1290 expressions were notably enhanced in HUVECs mediated by IL-8. miR-1290 inhibitor repressed monocytic THP-1 cells adhesion to HUVECs by regulating ICAM-1 and VCAM-1, inhibited proliferation through regulating cyclinD1 and PCNA, and inhibited inflammatory response by regulating IL-1β. Mechanistically, we verified that miR-1290 mimic was able to directly target the 3'-UTR of GSK-3β mRNA using luciferase reporter assay. Knockdown of GSK-3β (si-GSK-3β) promoted HUVECs adhesion and the expression of IL-1β, and partially restore the depression effect of miR-1290 inhibitor on HUVECs adhesion and inflammation. In contrast, si-GSK-3β inhibited the proliferation of HUVECs and the expression of cyclinD1 and PCNA. In summary, our study revealed that miR-1290 promotes IL-8-mediated the adhesion of HUVECs by targeting GSK-3β. However, GSK-3β is not the target protein for miR-1290 to regulate the proliferation of HUVECs. Our findings may provide potential target in atherosclerosis treatment.

Biomaterial-induced conversion of quiescent cardiomyocytes into pacemaker cells in rats.

Pacemaker cells can be differentiated from stem cells or transdifferentiated from quiescent mature cardiac cells via genetic manipulation. Here we show that the exposure of rat quiescent ventricular cardiomyocytes to a silk-fibroin hydrogel activates the direct conversion of the quiescent cardiomyocytes to pacemaker cardiomyocytes by inducing the ectopic expression of the vascular endothelial cell-adhesion glycoprotein cadherin. The silk-fibroin-induced pacemaker cells exhibited functional and morphological features of genuine sinoatrial-node cardiomyocytes in vitro, and pacemaker cells generated via the injection of silk fibroin in the left ventricles of rats functioned as a surrogate in situ sinoatrial node. Biomaterials with suitable surface structure, mechanics and biochemistry could facilitate the scalable production of biological pacemakers for human use.

Abstract 13231: Semaphorin3F Reduces Atherosclerosis by Decreasing Endothelial Activation and Barrier Permeability and Smooth Muscle Cell Migration

Coronary artery disease (CAD) remains a leading cause of death worldwide. To identify genes causally linked to CAD, we previously conducted large-scale genetic analyses, and identified an association between genes in the semaphorin pathway and CAD. Expression profiling in human atherosclerosis-relevant cell types and atherosclerotic plaques identified semaphorin3F (SEMA3F) as a possible candidate causally linked to atherosclerosis. Administration of SEMA3F reduced aortic lesion area in western-type diet-fed Ldlr -/- mice (Control: 12.1±1.4; SEMA3F: 8.1±0.8, % lesion area/total aortic sinus area, p=0.02). In contrast, neointimal formation was increased in Sema3f -/- mice with partial carotid artery ligation ( WT : 22.8±2.8; Sema3f -/- : 39.2±4.0; % intimal area/total vessel area, p=0.004). Additionally, SEMA3F administration increased re-endothelialization and reduced restenosis in Ldlr -/- mice that underwent carotid endothelial denudation (Control: 53.3±3.5; SEMA3F: 21.4±3.1; % intimal plaque area/vessel area, p=0.0006). Monocyte adhesion to aortic vascular endothelial cells (VECs) from Sema3f -/- mice was elevated, driven by increased NF-κB activation and increased expression of its target adhesion molecules, VCAM1 and ICAM1, in VECs. Monocyte transmigration through VECs from Sema3f -/- mice was also increased, likely due to increased membrane permeability, assessed by in-vivo intravital two-photon microscopy. The increased membrane permeability was modulated in part by decreased mTOR phosphorylation that in turn suppressed vascular endothelial cadherin protein expression. SEMA3F increased thick actomyosin filaments and elicited larger focal adhesions in VECs, suggesting decreased migration. In line with this, SEMA3F inhibited vascular smooth muscle cell (VSMC) migration and maintained the contractile phenotype of VSMCs, which was mediated by the Rho pathway. SEMA3F is causally atheroprotective in models of atherosclerosis and restenosis, mediated, in part, through the modulation of vascular endothelial cell permeability and adhesion molecule expression, and vascular smooth muscle cell migration and phenotype switching.