scholarly journals Sustained Release of MiR-217 Inhibitor by Nanoparticles Facilitates MSC-Mediated Attenuation of Neointimal Hyperplasia After Vascular Injury

2021 ◽  
Vol 8 ◽  
Author(s):  
Hong Yu ◽  
Yutao Hua ◽  
Yecheng He ◽  
Yin Wang ◽  
Xingjian Hu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sustained Release ◽  
Vascular Injury ◽  
Therapeutic Potential ◽  
Neointimal Hyperplasia ◽  
Endothelial Differentiation ◽  
Vascular Density ◽  
Therapeutic Effects ◽  
Neointimal Proliferation ◽  
And Migration

Mesenchymal stem cells (MSCs) have been proven capable of differentiating into endothelial cells (ECs) and increasing vascular density in mouse ischemia models. However, the therapeutic potential of MSCs in neointimal hyperplasia after vascular injury is still not fully understood. In this study, we proposed that sustained release of miR-217 inhibitor encapsulated by nanoparticles in MSCs can enhance the therapeutic effects of MSCs on alleviating neointimal hyperplasia in a standard mouse wire injury model. We intravenously administered MSCs to mice with injured arteries and examined neointimal proliferation, endothelial differentiation and senescence. We demonstrated that MSCs localized to the luminal surface of the injured artery within 24 h after injection and subsequently differentiated into endothelial cells, inhibited neointimal proliferation and migration of vascular smooth muscle cells. Transfection of MSCs with poly lactic-co-glycolic acid nanoparticles (PLGA-NP) encapsulating an miR-217 agomir abolished endothelial differentiation as well as the therapeutic effect of MSCs. On the contrary, silencing of endogenous miR-217 improved the therapeutic efficacy of MSCs. Our study provides a new strategy of augmenting the therapeutic potency of MSCs in treatment of vascular injury.

Abstract 1126: Adiponectin Prevents Neointimal Hyperplasia After Vascular Injury In Adiponectin Transgenic Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
yasutoshi omori
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Injury ◽  
Tissue Concentration ◽  
Adiponectin Level ◽  
Neointimal Hyperplasia ◽  
Intercellular Adhesion Molecule ◽  
Morphometrical Analysis ◽  
Anti Body

Background: Adiponectin has been reported to accumulate in the human injured artery and regulate the development of atherosclerosis, decreasing the expression of adhesion molecules in vascular endothelial cells, and inhibiting the proliferation of vascular smooth muscle cells. However, the role of adiponection after vascular injury is not fully elucidated. Therefore, we investigate whether adiponectin prevents neointimal hyperplasia after vascular injury in adiponectin transgenic mice (TG). Methods: C57/BL6 mice (WT) and TG of 6 –7 week age were used. We inserted a large wire (0.38 mm in diameter) into femoral artery from distal side to proximal side to make the vascular endothelium damaged model. Mice were sacrificed at 1, 2 and 4 weeks, and non injured mice were used as control. Tissue concentration of fat and liver and serum concentration of adiponectin was measured using ELISA. Intima/ media ratio was measured in morphometrical analysis. Immunohistochemical staining of anti-adiponectin, anti-α-smooth muscle embryo (α-SMemb), anti-α-smooth muscle cell actin, von Willebrand Factor (vWF) and intercellular adhesion molecule-1 (ICAM-1) was performed using paraffin embedded sections. Result: In immunohistochemical analysis at 1 week, α-SMemb positive cells, which were also positive for ICAM-1 were observed in WT, but were not seen in TG. Adiponectin positive cells, which were also positive for vWF were observed in the endothelial cells in TG, but were not detected in WT at 1 week, but those cells were observed in th endothelial cells in TG and WT at 2 and 4 weeks. In α-SMA staining at 4 weeks most neointimal area was stained with this anti-body in TG. On the other hand, in neointima of WT, only some area was stained with this anti-body. In morphometrical analysis, intima/media ratio was significantly smaller in TG than in WT at 1, 2 and 4 weeks. Adiponectin concentration of fat, liver and serum was significantly higher in TG than in WT in non-injured model and at 4 weeks. At 1 week liver and fat adiponectin level is significantly higher in TG than in WT, and serum adiponectin level in TG tended to be high as compared to that of WT. Conclusions: Adiponectin prevents neointimal hyperplasia after vascular injury, probably through the inhibition of inflammatory reaction.

scholarly journals 2194

2017 ◽  
Vol 1 (S1) ◽  
pp. 3-3
Author(s):  
Michael Khanjyan ◽  
Vien Nguyen ◽  
Eric Kazangian ◽  
Shane Browne ◽  
Kevin Healy ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Therapeutic Potential ◽  
Time Dependent ◽  
Endothelial Differentiation ◽  
Cardiac Stem Cell ◽  
Study Population ◽  
Hydrogel System

OBJECTIVES/SPECIFIC AIMS: A major limitation of cardiac stem cell transplantation following myocardial infarction (MI) is poor retention of cells in the ischemic microenvironment. Our study aims to better understand and promote the survival and differentiation of human cardiosphere-derived cells (hCDCs) in anoxia, a feature of infarcted myocardium. METHODS/STUDY POPULATION: We previously demonstrated that TGFβ1 and heparin-containing hydrogels (TH-hydrogel) can promote murine CDC survival. In this study, hCDCs were incubated in either normoxia or anoxia for 8 hours with and without TH-hydrogel. In addition, hCDCs without TH-hydrogel were assessed in 16 hours of anoxia. Following incubation, hCDCs were assayed for viability using calcein dye and immunostained for CD31, a marker of endothelial differentiation. RESULTS/ANTICIPATED RESULTS: hCDCs incubated for 8 hours in anoxia in both models equally demonstrated increased survival up to 30% when compared with cells incubated in normoxia. However, in contrast to hCDCs alone, hCDCs with TH-hydrogel additionally demonstrated increased differentiation into endothelial cells in both anoxia and normoxia. We found that hCDCs alone were able to upregulate CD31 only when subjected to 16 hours of anoxia. DISCUSSION/SIGNIFICANCE OF IMPACT: We demonstrate a new, previously unknown response of hCDCs to anoxia. This induces increased viability and differentiation of hCDCs into endothelial cells. The differentiation in anoxia was time dependent and could be expedited with use of TH-hydrogel. Anoxic preconditioning of hCDCs together with the TH-hydrogel system may improve the therapeutic potential of stem cell transplantation following MI.

scholarly journals miR-214-3p-Sufu-GLI1 is a novel regulatory axis controlling inflammatory smooth muscle cell differentiation from stem cells and neointimal hyperplasia

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shiping He ◽  
Feng Yang ◽  
Mei Yang ◽  
Weiwei An ◽  
Eithne Margaret Maguire ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Therapeutic Potential ◽  
Neointimal Hyperplasia ◽  
Consensus Sequence ◽  
Nuclear Accumulation ◽  
Therapeutic Effects ◽  
Gene Promoters ◽  
Site Mutation ◽  
Human Arteries

Abstract Background Inflammatory smooth muscle cells (iSMCs) generated from adventitial stem/progenitor cells (AdSPCs) have been recognised as a new player in cardiovascular disease, and microRNA-214-3p (miR-214-3p) has been implicated in mature vascular SMC functions and neointimal hyperplasia. Here, we attempted to elucidate the functional involvements of miR-214-3p in iSMC differentiation from AdSPCs and unravel the therapeutic potential of miR-214-3p signalling in AdSPCs for injury-induced neointimal hyperplasia. Methods The role of miR-214-3p in iSMC differentiation from AdSPCs was evaluated by multiple biochemistry assays. The target of miR-214-3p was identified through binding site mutation and reporter activity analysis. A murine model of injury-induced arterial remodelling and stem cell transplantation was conducted to study the therapeutic potential of miR-214-3p. RT-qPCR analysis was performed to examine the gene expression in healthy and diseased human arteries. Results miR-214-3p prevented iSMC differentiation/generation from AdSPCs by restoring sonic hedgehog-glioma-associated oncogene 1 (Shh-GLI1) signalling. Suppressor of fused (Sufu) was identified as a functional target of miR-214-3p during iSMC generation from AdSPCs. Mechanistic studies revealed that miR-214-3p over-expression or Sufu inhibition can promote nuclear accumulation of GLI1 protein in AdSPCs, and the consensus sequence (GACCACCCA) for GLI1 binding within smooth muscle alpha-actin (SMαA) and serum response factor (SRF) gene promoters is required for their respective regulation by miR-214-3p and Sufu. Additionally, Sufu upregulates multiple inflammatory gene expression (IFNγ, IL-6, MCP-1 and S100A4) in iSMCs. In vivo, transfection of miR-214-3p into the injured vessels resulted in the decreased expression level of Sufu, reduced iSMC generation and inhibited neointimal hyperplasia. Importantly, perivascular transplantation of AdSPCs increased neointimal hyperplasia, whereas transplantation of AdSPCs over-expressing miR-214-3p prevented this. Finally, decreased expression of miR-214-3p but increased expression of Sufu was observed in diseased human arteries. Conclusions We present a previously unexplored role for miR-214-3p in iSMC differentiation and neointima iSMC hyperplasia and provide new insights into the therapeutic effects of miR-214-3p in vascular disease.

Abstract 5492: Tetrahydrobiopterin (BH4) Improves Endothelial Cell Survival After Vascular Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruth Rinze ◽  
Ziad A Ali ◽  
Gillian Douglas ◽  
Nicholas J Alp ◽  
Keith M Channon
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Survival ◽  
Vascular Injury ◽  
Neointimal Hyperplasia ◽  
Wild Type ◽  
Endothelial Cell Survival ◽  
Apoe Ko Mice ◽  
Apoe Ko

Endothelial cell loss, survival and regeneration are important aspects of the response to vascular injury leading to neointimal hyperplasia and accelerated atherosclerosis. Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is a key regulator of endothelial cell biology and has been shown to prevent endothelial cell apoptosis. The cofactor tetrahydrobiopterin (BH4) is essential for eNOS catalytic activity but its impact on endothelial cell survival and regeneration remains unclear. We investigated the effect of BH4 on endothelial cell survival and vascular remodelling using ApoE-KO mice with transgenic endothelial-targeted overexpression of GTP cyclohydrolase 1 (GCH), the rate limiting enzyme of BH4 synthesis, and with endothelial specific transgenic expression of the LacZ reporter gene. Using venous bypass grafts as an in vivo model of acute vascular injury, we observed that endothelial-specific augmentation of BH4 in GCH/ApoE-KO mice improved survival of vein graft-derived endothelial cells and reduced neointimal hyperplasia. To address the hypothesis that augmentation of BH4 increases the capacity of endothelial cells from GCH/ApoE-KO mice to survive vascular injury, we cultured primary lung endothelial cells from mice expressing the GCH transgene and wild type littermates. Endothelial cells, isolated by immunomagnetic beads, were positive for CD31, CD102 and Tie2. Protein levels of eNOS were not different between wild type and GCH mice. BH4 levels were selectively increased in pulmonary endothelial cells from GCH mice, > 10-fold, compared with a 3-fold increase in total lung tissue BH4. There was no difference in total lung endothelial cell content or amount of isolated cells between ApoE-KO and GCH/ApoE-KO mice, determined by Tie2-driven β-galactosidase activity. However, after 3 days of culture both total endothelial cell number and number of endothelial cell colonies in GCH/ApoE-KO were significantly increased (236% ± 47 p=0.028 and 195% ± 28 p=0.014 respectively, n=5) whereas mean colony size remained unchanged. These observations indicate an important role for BH4 in endothelial cell survival and endothelial regeneration, and identify BH4 as a potential therapeutic target in vascular injury states.

scholarly journals Endothelial Cells Regulate Cardiac Myocyte Reorganisation Through β1-Integrin Signalling

2015 ◽  
Vol 35 (5) ◽  
pp. 1808-1820 ◽  
Author(s):  
Yu Zhang ◽  
Hai Li ◽  
Renyue Wei ◽  
Jing Ma ◽  
Yanhua Zhao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Cardiomyopathy ◽  
Cardiac Myocyte ◽  
Cardiac Development ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Scar Tissue ◽  
Β1 Integrin ◽  
Myocardial Repair ◽  
And Migration

Background: In normal hearts, capillaries are densely distributed throughout the myocardial tissue, and the cross-talk between myocytes and capillary endothelial cells plays a pivotal role in regulating cardiac development, maturation and function. Although previous studies have suggested a role for the endothelium in the organisation of nearby cardiomyocytes, the underlying mechanism has yet to be illustrated. Methods and Results: Using a transwell coculture system, we studied the paracrine effect of endothelial cells on cardiomyocytes and found that the regulation of cardiomyocyte spatial reorganisation and cytoskeletal dynamics by endothelial cells was coupled with β1-integrin induction. To determine the role of β1-integrin in this process, we preincubated myocytes with a β1-integrin function-blocking antibody before coculture. β1-integrin blockage abolished myocyte chemotactic activity and inhibited microtubule extension and stress fibre assembly. We further evaluated the therapeutic potential of combined endothelial cell-cardiac myocyte transplantation against ischemic cardiomyopathy in an acute myocardial infarction (AMI) mouse model. The results showed that myocytes and endothelial cells synergistically promoted ischemic myocardial repair, as evidenced by the robust engraftment and migration of implanted cells within the infarcted area, as well as the stimulation of angiogenesis, the attenuation of scar tissue and the improvement of cardiac function. Conclusion: Our study demonstrated the necessity of β1-integrin in the interactions between cardiomyocytes and endothelial cells and presented a novel combined transplantation approach that might hold promise for treating ischemic cardiomyopathy.

Platelet-Derived Exosomes Affect the Proliferation and Migration of Human Umbilical Vein Endothelial Cells Via miR-126

2019 ◽  
Vol 17 (4) ◽  
pp. 379-387 ◽  
Author(s):  
Yan Sun ◽  
Xiao-li Liu ◽  
Dai Zhang ◽  
Fang Liu ◽  
Yu-jing Cheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Real Time ◽  
Umbilical Vein ◽  
Angiogenic Factors ◽  
Healthy Donors ◽  
And Migration ◽  
Umbilical Vein Endothelial Cells ◽  
Tgf Β1 ◽  
Proliferation And Migration

Background:Intraplaque angiogenesis, the process of generating new blood vessels mediated by endothelial cells, contributes to plaque growth, intraplaque hemorrhage, and thromboembolic events. Platelet-derived Exosomes (PLT-EXOs) affect angiogenesis in multiple ways. The ability of miR-126, one of the best-characterized miRNAs that regulates angiogenesis, carried by PLT-EXOs to influence angiogenesis via the regulation of the proliferation and migration of endothelial cells is unknown. In this study, we aimed to investigate the effects of PLT-EXOs on angiogenesis by Human Umbilical Vein Endothelial Cells (HUVECs).Methods:We evaluated the levels of miR-126 and angiogenic factors in PLT-EXOs from Acute Coronary Syndrome (ACS) patients and healthy donors by real-time Polymerase Chain Reaction (PCR) and western blotting. We incubated HUVECs with PLT-EXOs and measured cell proliferation and migration with the Cell Counting Kit-8 assay and scratch assay, respectively. We also investigated the expression of miR-126 and angiogenic factors in HUVECs after exposure to PLT-EXOs by western blotting and real-time PCR.Results:PLT-EXOs from ACS patients contained higher levels of miR-126 and angiogenic factors, including Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF), and Transforming Growth Factor Beta 1 (TGF-β1), than those from healthy donors (p<0.05). Moreover, the levels of exosomal miR-126 and angiogenic factors were increased after stimulation with thrombin (p<0.01). HUVEC proliferation and migration were promoted by treatment with activated PLT-EXOs (p<0.01); they were accompanied by the over-expression of miR-126 and angiogenic factors, including VEGF, bFGF, and TGF-β1 (p<0.01).Conclusion:Activated PLT-EXOs promoted the proliferation and migration of HUVECs, and the overexpression of miR-126 and angiogenic factors, thereby elucidating potential new therapeutic targets for intraplaque angiogenesis.

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