ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Zhang Bu-chun,Zhu Wen-ya,Wang Sheng-nan,Zhu Meng-meng,Ma Hui,Dong Liang,Yang Xiao-xiao,Ma Chuan-rui,Ma Li-kun,Chen Yuan-li
Vascular smooth muscle cell (VSMC) phenotype transformation significantly contributes to vascular intimal hyperplasia. However, effective preventive and therapeutic measures are lacking. Colchicine, a binary alkaloid derived from Colchicum autumnale , is traditionally used for treating inflammatory diseases. Its role in neointima formation is not fully understood. Here, we investigated the role of colchicine in vascular intimal hyperplasia. We found that colchicine significantly reduced vascular intimal hyperplasia in an animal model at 7, 14, and 28 days post carotid artery ligation and increased the number of contractile-phenotype VSMCs (SMA-positive cells) in the neointimal areas. In vitro experiments demonstrated that colchicine facilitated the transition of VSMCs from a proliferative phenotype to a contractile phenotype. Additionally, colchicine attenuated PDGF-BB-induced phenotypic conversion and upregulated the expression of serum response factor (SRF) and myocardin (MYOCD). Further molecular mechanistic studies revealed that colchicine inhibited the expression of forkhead box protein O3A (FOXO3A) to increase the activation of the SRF‒MYOCD complex. FOXO3A can bind to MSX1/2, thereby inhibiting the expression of SRF–MYOCD and contractile genes. Moreover, colchicine maintains vascular homeostasis and stabilizes the contractile phenotype by affecting the expression of autophagy-related genes (LC3II, p62, and Beclin-1) induced by FOXO3A. Additionally, colchicine inhibited monocyte/macrophage infiltration and inflammatory cytokine expression. In summary, this study suggests that colchicine inhibits vascular intimal hyperplasia by modulating FOXO3A-mediated SRF-MYOCD activation and autophagy, providing new insights for future therapeutic approaches targeting occlusive vascular diseases.
研究领域:
药理学
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心血管疾病
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2021
·
IF 14.593
Qing Ma,Xiuying Shi,Xing Tan,Rui Wang,Kaiqin Xiong,Manfred F. Maitz,Yuanyuan Cui,Zhangmei Hu,Qiufen Tu,Nan Huang,Li Shen,Zhilu Yang
Mimicking the nitric oxide (NO)-release and glycocalyx functions of native vascular endothelium on cardiovascular stent surfaces has been demonstrated to reduce in-stent restenosis (ISR) effectively. However, the practical performance of such an endothelium-mimicking surfaces is strictly limited by the durability of both NO release and bioactivity of the glycocalyx component. Herein, we present a mussel-inspired amine-bearing adhesive coating able to firmly tether the NO-generating species (e.g., Cu-DOTA coordination complex) and glycocalyx-like component (e.g., heparin) to create a durable endothelium-mimicking surface. The stent surface was firstly coated with polydopamine (pDA), followed by a surface chemical cross-link with polyamine (pAM) to form a durable pAMDA coating. Using a stepwise grafting strategy, Cu-DOTA and heparin were covalently grafted on the pAMDA-coated stent based on carbodiimide chemistry. Owing to both the high chemical stability of the pAMDA coating and covalent immobilization manner of the molecules, this proposed strategy could provide 62.4% bioactivity retention ratio of heparin, meanwhile persistently generate NO at physiological level from 5.9 ± 0.3 to 4.8 ± 0.4 × 10 −10 mol cm −2 min −1 in 1 month. As a result, the functionalized vascular stent showed long-term endothelium-mimicking physiological effects on inhibition of thrombosis, inflammation, and intimal hyperplasia, enhanced re-endothelialization, and hence efficiently reduced ISR.
研究领域:
生物医学工程
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材料科学
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心脏病学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Jiayin Fu,Ning Zhang,Changfu Xu,Meng Zhao,Shaofei Wu,Shihui Xu,Xulin Hong,Meihui Wang,Guosheng Fu
Synthetic vascular grafts are promising conduits for small caliber arteries. However, due to restenosis caused by intimal hyperplasia, they cannot keep long patency in vivo. In this work, through single cell RNA sequencing, we found that thrombospondin-1 (THBS1) was highly expressed in the regenerated smooth muscle cells (SMCs) in electrospun polycaprolactone (PCL) vascular grafts. The expression of THBS1 by injured SMCs was confirmed in a balloon-induced vascular injury model. Downregulation of Thbs1 expression maintained contractile phenotypes of SMCs and reduced neointimal hyperplasia after vascular injury via inhibition of FGFR1/EGR1 signaling by decreasing THBS1 expression. THBS1 small interfering RNA (THBS1-siRNA) was then loaded into macrophage membrane (MM) hybrid lipid nanoparticles (Lipid NP@MM), which were used to modify PCL vascular grafts via polydopamine (PDA) coatings. Lipid NP@MM not only protected THBS1-siRNA from degradation but also improved its internalization by SMCs to decrease the level of THBS1 expression. PCL vascular grafts modified with PDA coatings and Thbs1-siRNA-loaded Lipid NP@MM showed significantly reduced intimal hyperplasia. Thus, the downregulation of THBS1 expression in regenerated SMCs in vascular grafts is a promising strategy to inhibit intimal hyperplasia during vascular graft regeneration in vivo.
研究领域:
生物材料
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组织工程
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血管生物学
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分子生物学
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纳米技术
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Pharmaceutics-X
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2024
·
IF 5.2
Fajing Yang,Yihui Qiu,Xueting Xie,Xingjian Zhou,Shunfu Wang,Jialu Weng,Lina Wu,Yizhe Ma,Ziyue Wang,Wenzhang Jin,Bicheng Chen
Autologous vein grafts have attracted widespread attention for their high transplantation success rate and low risk of immune rejection. However, this technique is limited by the postoperative neointimal hyperplasia, recurrent stenosis and vein graft occlusion. Hence, we propose the platelet membrane-coated Poly(lactic- co -glycolic acid) (PLGA) containing sildenafil (PPS). Platelet membrane (PM) is characterised by actively targeting damaged blood vessels. The PPS can effectively target the vein grafts and then slowly release sildenafil to treat intimal hyperplasia in the vein grafts, thereby preventing the progression of vein graft restenosis. PPS effectively inhibits the proliferation and migration of vascular smooth muscle cell (VSMCs) and promotes the migration and vascularisation of human umbilical vein endothelial cells (HUVECs). In a New Zealand rabbit model of intimal hyperplasia in vein grafts, the PPS significantly suppressed vascular stenosis and intimal hyperplasia at 14 and 28 days after surgery. Thus, PPS represents a nanomedicine with therapeutic potential for treating intimal hyperplasia of vein grafts.
研究领域:
纳米技术
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药理学
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心血管医学
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生物材料科学
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组织工程
✓ 已验证
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
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IF 9.6
Jie Zhang,Yanlong Wang,Yu Sun,Zeyi Zhou,Fengni Liu,Xinyu Zhang,Chuiyu Kong,Jiang Yuan,Meng Yin,Dongjin Wang
Intimal hyperplasia, thrombosis formation, and vascular calcification are the leading causes of failure in small-diameter vascular grafts. In the study, bilayer vascular grafts with separately released nitric oxide (NO) and resveratrol (RESV) were fabricated. S-nitrosated keratin nanoparticles (KNPs) were synthesized and subsequently electrospun with polycaprolactone (PCL) to prolong the NO release for up to 25 d in the presence of ascorbic acid and trypsin, serving as the inner layer of grafts. Additionally, RESV was incorporated into poly(ε-caprolactone-co-L-lactide) (PLCL) fibers to alleviate oxidative stress and inflammation, acting as the outer layer of the grafts. The PCL/KNPs//PLCL/RESV bilayer grafts were capable of promoting endothelial cell proliferation while inhibiting the excessive proliferation of smooth muscle cells. Notably, bilayer grafts could regulate macrophage polarization toward the M2 phenotype. In rat abdominal aorta replacement models, the grafts retained patency for 3 months. These grafts could accelerate endothelialization without apparent intimal hyperplasia, thrombosis, inflammation, and calcification. These bilayer grafts are promising for small-diameter tissue-engineered vascular grafts. Statement of Significance • S-nitrosated keratin nanoparticles (KNPs) were synthesized and subsequently electrospun to prolong the NO release for 25 d. • Resveratrol (RESV) was incorporated into PLCL fibers to alleviate oxidative stress and inflammation. • Bilayer grafts promoted EC proliferation while inhibiting SMC proliferation. • Bilayer grafts accelerated endothelialization without intimal hyperplasia, thrombosis, and calcification in vivo.
研究领域:
生物材料
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组织工程
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纳米技术
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心血管医学
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Hui Yan,Lietao Wang,Haoshuang Wu,Yongqi An,Yumei Qin,Zhen Xiang,Huining Wan,Yanfei Tan,Li Yang,Fanjun Zhang,Qing Jiang,Rifang Luo,Yunbing Wang
Unhealthy vascular tissue healing after stenting is primarily triggered by endothelial dysfunction and excessive smooth muscle cell proliferation, which is induced and aggravated by local thrombosis and excessive inflammation. Excessive inflammatory response is closely related to elevated concentrations of reactive oxygen species (ROS). Here, an environment-friendly coating strategy termed “Anti-fouling plus” with inflammatory self-regulation ability was proposed. Upon this, membrane-mimicking copolymer MA(PCLA) served as the antifouling coating, effectively inhibiting coagulation and inflammation during the early stage of implantation. Furthermore, a ROS-responsive prodrug was drawn into the coating to promote tissue healing. A molecular prodrug of thioketal-bearing dexamethasone was engineered to be released in a controlled and responsive manner in response to externally high levels of ROS. The released dexamethasone exhibited highly effective anti-inflammation properties after implantation. The combination of ROS-responsive prodrug and membrane-mimicking antifouling interface strategy intelligently integrated inflammation responsiveness and regulation, which could mediate a gentle vascular microenvironment and thus promote vascular remodeling. In vivo stent implantation studies demonstrated that the proposed “Anti-fouling plus” coating effectively inhibited neointima hyperplasia, modulated the inflammatory response and promoted endothelialization, offering promising surface modification approaches for vascular stents.
研究领域:
生物材料
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组织工程
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血管生物学
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
Biomaterials Advances
·
2022
·
IF 0
Shihui Liu,Junchao Zhi,Yao Chen,Zhuoyue Song,Lin Wang,Chunzhi Tang,Shijie Li,Xiaoping Lai,Nenggui Xu,Tao Liu
Vascular stents are widely used in the clinical treatment of coronary heart disease, but the long-term safety still needs to be improved. Surface biological functional modification is an effective way to improve the biocompatibility and clinical performance of cardiovascular materials, but how to achieve long-term effective and precise regulation of in situ vascular intimal repair through the reasonable construction of the surface physical and chemical structure is still an important task in the current surface modification research. In this study, ECM-derived components, including laminin, heparin, and SDF-1, were incorporated into the titanium surface with a microporous structure. It was found that the modified surface could effectively control the continuous release of biomolecules. In vitro biocompatibility evaluation results showed that the constructed functional layer could effectively inhibit the activation of platelet adhesion and excessive proliferation of smooth muscle cells. In addition, the modified surface also showed the potential to induce rapid regeneration of vascular endothelium. In vivo animal tests further proved that the modified sample may contribute to inhibiting vascular intimal hyperplasia. This study provided a new approach for the surface biological function modification of Ti-based vascular stents.
研究领域:
生物医学工程
·
材料科学
·
心血管医学
·
组织工程
✓ 已验证
DOI
PubMed
Regenerative Biomaterials
·
2024
·
IF 5.6
Xie Yinhong,Chi Mengchen,Yang Xinlei,Dong Ruichen,Yang Ao,Yin Antao,Weng Yajun
Modification of polylactic acid (PLA) is a promising strategy for the next generation of bioresorbable vascular stent biomaterials. With this focus, FeMOFs nanoparticles was incorporated in PLA, and then post loading of CO was performed by pressurization. It showed FeMOFs incorporation increased hydrophilicity of the surface and CO loading, and CO release was sustained at least for 3d. It is well acknowledged NETosis and macrophage mediated inflammation are the principal effectors of atherosclerosis and cardiovascular disease, and it further increases the risk of late stent thrombosis and restenosis. In this study, the effects of CO release of PLA/FeMOFs/CO on NETosis and macrophage behavior were thoroughly explored. In vitro evaluation results showed that PLA/FeMOFs/CO significantly inhibited neutrophil extracellular traps (NETs) release and neutrophil elastase (NE) expression by reducing intracellular ROS in a simulated inflammatory environment. It reduced LPS-induced macrophage inflammation with decreased TNF-α expression and increased IL-10 expression. Meanwhile it enhanced endothelial cell activity and growth in inflammatory environment, and inhibited platelet adhesion and activation. In vivo implantation results confirmed that PLA/FeMOFs/CO reduced the macrophages and neutrophils mediated inflammatory response, thus reduced the neointimal hyperplasia. Overall, PLA/FeMOFs/CO effectively prevented the inflammation and restenosis associated with PLA implantation. Our study provides a new strategy to improve the immunocompatibility of PLA implant materials.
研究领域:
生物材料
·
心血管工程
·
免疫学
·
组织工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2022
·
IF 6.064
Yaping Shan,Gang Chen,Qiqi Shi,Jiaxi Huang,Yaping Mi,Wenbo Zhang,Huifeng Zhang,Bing Jia
Prosthetic implants of expanded polytetrafluoroethylene (ePTFE) in the cardiovascular system have a high failure rate over the long term because of thrombosis and intimal hyperplasia. Although multiple surface modification methods have been applied to improve the anti-thrombotic and in situ endothelialization abilities of ePTFE, none have delivered outstanding results in vivo . Our previous study combined heparin/collagen multilayers and REDV peptides to modify ePTFE, and the in-vitro results showed that modification ePTFE with heparin/collagen-REDV can promote the cytocompatibility and antiplatelet property. This study illustrated the physical change, selective endothelial cells capture ability, and in vivo performance in further. The physical test demonstrated that this modification improved the hydrophilicity, flexibility and strength of ePTFE. A competition experiment of co-cultured endothelial cells and vascular smooth muscle cells verified that the heparin/collagen-REDV modification had high specificity for endothelial cell capture. A rabbit animal model was constructed to evaluate the in vivo performance of modified ePTFE implanted in the right ventricular outflow tract. The results showed that heparin/collagen-REDV modification was safe, promoted endothelialization, and successfully achieved regional anti-thrombosis without influencing body-wide coagulation function. The pathologic manifestations and mRNA expression pattern in tissues in contact with modified ePTFE indicated that this modification method may reduce M2-type macrophage infiltration and the expression of genes related to immune and inflammatory responses. The heparin/collagen-REDV modification may lower the incidence of complications related to ePTFE implantation and has good prospects for clinical use.
研究领域:
生物材料
·
心血管工程
·
组织工程
·
生物医学工程
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
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