scholarly journals The P387 Thrombospondin-4 Variant Promotes Accumulation of Macrophages in Atherosclerotic Lesions

2019 ◽  
Author(s):  
Santoshi Muppala ◽  
Mohammed Tanjimur Rahman ◽  
Irene Krukovets ◽  
Dmitriy Verbovetskiy ◽  
Elzbieta Pluskota ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Smooth Muscle Actin ◽  
Vascular Inflammation ◽  
Cutting Temperature ◽  
Vascular Wall ◽  
Alpha Smooth Muscle Actin ◽  
Knock Out ◽  
Atherosclerotic Lesions ◽  
Thrombospondin 4

AbstractAimsThrombopspondin-4 (TSP4) is a pro-angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP variant, P387 TSP4, have been associated with cardiovascular disease.Macrophages are central to initiation and resolution of inflammation and development of atherosclerotic lesions, but the effects of the P387 TSP4 on macrophages remain essentially unknown. We examined the effects of the P387 TSP4 variant on macrophages in cell culture andin vivoin a murine model of atherosclerosis. Further, the levels and distributions of the twoTSP4 variants were assessed in human atherosclerotic arteries.Methods and ResultsInApoE−/−/P387-TSP4 knock-in mice, atherosclerotic lesions accumulated more macrophages than lesions bearing A387 TSP4. The levels of inflammatory markers were increased in lesions ofApoE−/−/P387-TSP4 knock-in mice compared toApoE−/−mice. Lesions in human arteries from individuals carrying the P387 variant had higher levels of TSP4 and higher macrophage accumulation. P387 TSP4 was more active in supporting adhesion of cultured human and mouse macrophages in experiments using recombinant TSP4 variants and in cells derived from P387-TSP4 knock-in mice.ConclusionsTSP4 supports the adhesion of macrophages and their accumulation in atherosclerotic lesions. P387 TSP4 is more active in supporting these pro-inflammatory events in the vascular wall, which may contribute to the increased association of P387 TSP4 with cardiovascular disease.AbbreviationsBSA, bovine serum albumin; DMSO, dimethyl sulfoxide; ECM, extracellular matrix;Thbs4−/−, thrombospondin-4 gene knock-out; WT, wild type; P387-TSP4 KI, P387TSP4knock-in mice; OCT, Optimum Cutting Temperature; vWF, von Willebrand factor; α-SMA, alpha-smooth muscle actin; Egr2, Early Growth Response 2; PBS, Phosphate Buffer saline; DMEM, Dulbecco’s Modified Eagle Medium.

Cold Plasma Treatment Promotes Full-thickness Healing of Skin Wounds in Murine Models

2021 ◽  
pp. 153473462110021
Author(s):  
Joon M. Jung ◽  
Hae K. Yoon ◽  
Chang J. Jung ◽  
Soo Y. Jo ◽  
Sang G. Hwang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Plasma Treatment ◽  
Cold Plasma ◽  
Smooth Muscle Actin ◽  
Treated Group ◽  
Control Group ◽  
Alpha Smooth Muscle Actin ◽  
Skin Wound Healing

Cold plasma can be beneficial for promoting skin wound healing and has a high potential of being effectively used in treating various wounds. Our aim was to verify the effect of cold plasma in accelerating wound healing and investigate its underlying mechanism in vitro and in vivo. For the in vivo experiments, 2 full-thickness dermal wounds were created in each mouse (n = 30). While one wound was exposed to 2 daily plasma treatments for 3 min, the other wound served as a control. The wounds were evaluated by imaging and histological analyses at 4, 7, and 11 days post the wound infliction process. Immunohistochemical studies were also performed at the same time points. In vitro proliferation and scratch assay using HaCaT keratinocytes and fibroblasts were performed. The expression levels of wound healing–related genes were analyzed by real-time polymerase chain reaction and western blot analysis. On day 7, the wound healing rates were 53.94% and 63.58% for the control group and the plasma-treated group, respectively. On day 11, these rates were 76.05% and 93.44% for the control and plasma-treated groups, respectively, and the difference between them was significant ( P = .039). Histological analysis demonstrated that plasma treatment promotes the formation of epidermal keratin and granular layers. Immunohistochemical studies also revealed that collagen 1, collagen 3, and alpha-smooth muscle actin appeared more abundantly in the plasma-treated group than in the control group. In vitro, the proliferation of keratinocytes was promoted by plasma exposure. Scratch assay showed that fibroblast exposure to plasma increased their migration. The expression levels of collagen 1, collagen 3, and alpha-smooth muscle actin were elevated upon plasma treatment. In conclusion, cold plasma can accelerate skin wound healing and is well tolerated.

scholarly journals mTOR inhibitors potentially reduce TGF-β2-induced fibrogenic changes in trabecular meshwork cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nozomi Igarashi ◽  
Megumi Honjo ◽  
Makoto Aihara
Keyword(s):  
Trabecular Meshwork ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Mtor Inhibitors ◽  
In Vivo Model ◽  
Type I ◽  
Fibrotic Response ◽  
Alpha Smooth Muscle Actin

AbstractWe examined the effects of mTOR inhibitors on the fibrotic response induced by transforming growth factor-beta2 (TGF-β2) in cultured human trabecular meshwork (hTM) cells. TGF-β2-induced expression of fibronectin, collagen type I, alpha 1 chain (COL1A1), and alpha-smooth muscle actin (αSMA) in hTM cells was examined in the presence or absence of mTOR inhibitors using quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The migration rates of hTM cells were examined in the presence of TGF-β2 with or without mTOR inhibitors. An in vitro study showed that the expression of fibronectin, COL1A1, and αSMA was upregulated by TGF-β2 treatment of hTM cells; such upregulation was significantly suppressed by mTOR inhibitors. The inhibitors significantly reduced the migration rate of TGF-β2-stimulated hTM cells. mTOR inhibitors may usefully reduce the fibrotic response of hTM cells and we may have to explore if it is also effective in in vivo model.

scholarly journals Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction

2019 ◽  
Vol 39 (10) ◽  
pp. 2168-2191 ◽  
Author(s):  
Bronson A. Haynes ◽  
Li Fang Yang ◽  
Ryan W. Huyck ◽  
Eric J. Lehrer ◽  
Joshua M. Turner ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Smooth Muscle Actin ◽  
Phenotypic Change ◽  
Alpha Smooth Muscle Actin ◽  
Mesenchymal Transition ◽  
Molecular Features ◽  
Endothelial To Mesenchymal Transition

Objective: Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin). We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors. Conclusions: We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.

scholarly journals Vascular Wall–Mesenchymal Stem Cells Differentiation on 3D Biodegradable Highly Porous CaSi-DCPD Doped Poly (α-hydroxy) Acids Scaffolds for Bone Regeneration

Nanomaterials ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 243 ◽  
Author(s):  
Monica Forni ◽  
Chiara Bernardini ◽  
Fausto Zamparini ◽  
Augusta Zannoni ◽  
Roberta Salaroli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
In Vitro Model ◽  
Smooth Muscle Actin ◽  
Vascular Wall ◽  
Porous Scaffolds ◽  
Alpha Smooth Muscle Actin ◽  
Vitro Model ◽  
Highly Porous

Vascularization is a crucial factor when approaching any engineered tissue. Vascular wall–mesenchymal stem cells are an excellent in vitro model to study vascular remodeling due to their strong angiogenic attitude. This study aimed to demonstrate the angiogenic potential of experimental highly porous scaffolds based on polylactic acid (PLA) or poly-e-caprolactone (PCL) doped with calcium silicates (CaSi) and dicalcium phosphate dihydrate (DCPD), namely PLA-10CaSi-10DCPD and PCL-10CaSi-10DCPD, designed for the regeneration of bone defects. Vascular wall–mesenchymal stem cells (VW-MSCs) derived from pig thoracic aorta were seeded on the scaffolds and the expression of angiogenic markers, i.e. CD90 (mesenchymal stem/stromal cell surface marker), pericyte genes α-SMA (alpha smooth muscle actin), PDGFR-β (platelet-derived growth factor receptor-β), and NG2 (neuron-glial antigen 2) was evaluated. Pure PLA and pure PCL scaffolds and cell culture plastic were used as controls (3D in vitro model vs. 2D in vitro model). The results clearly demonstrated that the vascular wall mesenchymal cells colonized the scaffolds and were metabolically active. Cells, grown in these 3D systems, showed the typical gene expression profile they have in control 2D culture, although with some main quantitative differences. DNA staining and immunofluorescence assay for alpha-tubulin confirmed a cellular presence on both scaffolds. However, VW-MSCs cultured on PLA-10CaSi-10DCPD showed an individual cells growth, whilst on PCL-10CaSi-10DCPD scaffolds VW-MSCs grew in spherical clusters. In conclusion, vascular wall mesenchymal stem cells demonstrated the ability to colonize PLA and PCL scaffolds doped with CaSi-DCPD for new vessels formation and a potential for tissue regeneration.

scholarly journals Leukotriene Receptors: Crucial Components in Vascular Inflammation

2007 ◽  
Vol 7 ◽  
pp. 1422-1439 ◽  
Author(s):  
Magnus Bäck
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Inflammation ◽  
Vascular Wall ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Surface Receptors ◽  
Beneficial Effects

The accumulation of immune cells during vascular inflammation leads to formation of leukotrienes (LTs). While macrophages represent a major source of LT biosynthesis in the proximity of the vascular wall, activated T lymphocytes may, in addition, play a key regulatory role on macrophage expression of LT-forming enzymes. Within the vascular wall, LTs activate cell surface receptors of the BLT and CysLT subtypes expressed on vascular smooth muscle and endothelial cells. The LT receptor expression on those cells is highly dependent on transcriptional regulation by pro- and anti-inflammatory mediators. LT receptor activation on vascular smooth muscle cells is associated with both directly and indirectly induced vasoconstriction, as well as intimal hyperplasia through stimulation of migration and proliferation. On the other hand, endothelial LT receptors induce vasorelaxation and leukocyte recruitment and adhesion. Results fromin vitroandin vivostudies of LT receptor antagonists indicate potential beneficial effects in atherosclerosis and other inflammatory cardiovascular diseases.

scholarly journals Influence of Laminin Coating on the Autologous In Vivo Recellularization of Decellularized Vascular Protheses

Materials ◽  
2019 ◽  
Vol 12 (20) ◽  
pp. 3351 ◽  
Author(s):  
Mahfuza Toshmatova ◽  
Sentaro Nakanishi ◽  
Yukiharu Sugimura ◽  
Vera Schmidt ◽  
Artur Lichtenberg ◽  
...  
Keyword(s):  
Inflammatory Cell ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Similar Extent ◽  
Alpha Smooth Muscle Actin ◽  
Promising Strategy ◽  
Biological Implants ◽  
Significant Acceleration ◽  
The Media

Decellularization of non-autologous biological implants reduces the immune response against foreign tissue. Striving for in vivo repopulation of aortic prostheses with autologous cells, thereby improving the graft biocompatibility, we examined surface coating with laminin in a standardized rat implantation model. Detergent-decellularized aortic grafts from donor rats (n = 37) were coated with laminin and systemically implanted into Wistar rats. Uncoated implants served as controls. Implant re-colonization and remodeling were examined by scanning electron microscopy (n = 10), histology and immunohistology (n = 18). Laminin coating persisted over eight weeks. Two weeks after implantation, no relevant neoendothelium formation was observed, whereas it was covering the whole grafts after eight weeks, with a significant acceleration in the laminin group (p = 0.0048). Remarkably, the intima-to-media ratio, indicating adverse hyperplasia, was significantly diminished in the laminin group (p = 0.0149). No intergroup difference was detected in terms of medial recellularization (p = 0.2577). Alpha-smooth muscle actin-positive cells originating from the adventitial surface invaded the media in both groups to a similar extent. The amount of calcifying hydroxyapatite deposition in the intima and the media did not differ between the groups. Inflammatory cell markers (CD3 and CD68) proved negative in coated as well as uncoated decellularized implants. The coating of decellularized aortic implants with bioactive laminin caused an acceleration of the autologous recellularization and a reduction of the intima hyperplasia. Thereby, laminin coating seems to be a promising strategy to enhance the biocompatibility of tissue-engineered vascular implants.

scholarly journals n-3 Fatty acids prevent whereas trans-fatty acids induce vascular inflammation and sudden cardiac death

2009 ◽  
Vol 102 (12) ◽  
pp. 1811-1819 ◽  
Author(s):  
Rafat A. Siddiqui ◽  
Kevin A. Harvey ◽  
Nargiz Ruzmetov ◽  
Steven J. Miller ◽  
Gary P. Zaloga
Keyword(s):  
Fatty Acids ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Vascular Inflammation ◽  
Vascular Remodelling ◽  
Artery Ligation ◽  
Atherosclerotic Lesions ◽  
Collateral Growth

n-3 PUFA have well-recognised cardio-beneficial effects. In contrast, premature coronary deaths are associated with consumption of high levels of trans-fatty acids (TFA). The present study determined the effects of n-3 PUFA and TFA on sudden cardiac death and vascular inflammation. A rat coronary ligation model was used to study the effect of fatty acids on sudden cardiac death, whereas a mouse femoral artery ligation model was used to study compensatory vascular remodelling. Human aortic endothelial cells (HAEC) were utilised for the in vitro studies to investigate expression of inflammatory molecules. Feeding animals an n-3 PUFA-enriched diet caused a sevenfold increase in plasma n-3 PUFA compared with that of the TFA-fed group, whereas a TFA-enriched diet caused a 2·5-fold increase in plasma TFA compared with the n-3 PUFA group. Animals on a TFA diet had a lower survival rate due to sudden cardiac death and exhibited variable degrees of aortic atherosclerotic lesions. Animals on a TFA diet had diminished hindlimb collateral growth, whereas animals on the n-3 PUFA diet exhibited extensive collateral growth about ligated regions. HAEC treated with TFA (trans-18 : 2) showed significantly increased expression of intracellular adhesion molecule-1 and nitrosylation of cellular proteins than those treated with DHA (n-3 PUFA, 22 : 6). The in vivo study demonstrates that, in contrast to TFA, n-3 PUFA improve animal survival after myocardial infarction, prevent development of atherosclerotic lesions and stimulate compensatory vascular remodelling. The in vitro study demonstrates that TFA induce, while n-3 PUFA prevent, vascular inflammation.

scholarly journals Placental vascular remodeling in pregnant women with COVID-19

2021 ◽  
Author(s):  
Sergiy G. Gychka ◽  
Iurii L. Kuchyn ◽  
Tetyana V. Savchuk ◽  
Sofia I. Nikolaienko ◽  
Volodymyr M. Zhezhera ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Smooth Muscle Actin ◽  
Fold Increase ◽  
Vascular Wall ◽  
Host Cells ◽  
Wall Thickening ◽  
Alpha Smooth Muscle Actin ◽  
Angiotensin Converting Enzyme 2 ◽  
Smooth Muscle Proliferation

Severe acute respiratory syndrome coronavirus 2 has been causing the pandemic of coronavirus disease 2019 (COVID-19) that has so far resulted in over 180 million infections and nearly 4 million deaths. This respiratory virus uses angiotensin-converting enzyme 2 as a receptor to enter host cells, exhibiting a unique feature that affects various tissues in addition to the lungs. The present study reports that the placental arteries from women who gave birth to live full-term newborns while developing of COVID-19 during pregnancy exhibit severe vascular wall thickening and the occlusion of the vascular lumen. A morphometric analysis of the placental arteries stained with hematoxylin and eosin suggest a 2-fold increase in wall thickness and a 5-fold decrease in the lumen area. Immunohistochemistry with alpha-smooth muscle actin and Masson's trichrome staining showed that such placental vascular remodeling in COVID-19 is associated with smooth muscle proliferation and fibrosis. Placental vascular remodeling may represent a mechanism of the clinical problems associated with childbirth in COVID-19 patients.

scholarly journals In vivo recellularization of xenogeneic vascular grafts decellularized with high hydrostatic pressure method in a porcine carotid arterial interpose model

2020 ◽  
Author(s):  
Shunji Kurokawa ◽  
Yoshihide Hashimoto ◽  
Seiichi Funamoto ◽  
Akitatsu Yamashita ◽  
Kazuhiro Yamazaki ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hydrostatic Pressure ◽  
High Hydrostatic Pressure ◽  
Smooth Muscle Actin ◽  
Vascular Grafts ◽  
Graft Patency ◽  
Luminal Surface ◽  
Alpha Smooth Muscle Actin ◽  
Technical Improvement

ABSTRACTAutologous vascular grafts are widely used in revascularization surgeries for small caliber targets. However, the availability of autologous conduits might be limited due to prior surgeries or the quality of vessels. Xenogeneic decellularized vascular grafts from animals potentially substitute for autologous vascular grafts. Decellularization with high hydrostatic pressure (HHP) is reported to highly preserve extracellular matrix (ECM) which would be feasible for recellularization and vascular remodeling after implantation. In the present study, we conducted xenogeneic implantation of HHP-decellularized bovine vascular grafts from dorsalis pedis arteries to porcine carotid arteries then evaluated graft patency, ECM preservation and recellularization. Surgical procedure not to damage luminal surface of the grafts from drying significantly increased the graft patency at 4 weeks after implantation (P = 0.0079). After the technical improvement, all grafts (N = 5) were patent with mild stenosis due to intimal hyperplasia at 4 weeks after implantation. Neither aneurysmal change nor massive thrombosis was observed even without administration of anticoagulants nor anti-platelet agents. Elastica van Gieson and Sirius-red stainings revealed fair preservation of ECM proteins including elastin and collagen after implantation. Luminal surface of grafts was thoroughly covered with von Willebrand factor-positive endothelium. Scanning electron microscopy on luminal surface of implanted grafts exhibited cobblestone-like endothelial cell layer which is similar to native vascular endothelium. Recellularization of tunica media with alpha-smooth muscle actin-positive smooth muscle cells was partly observed. Thus, we confirmed that HHP-decellularized grafts are feasible for xenogeneic implantation accompanied by recellularization by recipient cells.

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