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Search Results (343)

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Keywords = aortic endothelial cells

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16 pages, 2130 KiB  
Article
A Distinct miRNA Profile in Intimal Hyperplasia of Failed Arteriovenous Fistulas Reveals Key Pathogenic Pathways
by Carmen Ciavarella, Francesco Vasuri, Alessio Degiovanni, Lena Christ, Raffaella Mauro, Mauro Gargiulo and Gianandrea Pasquinelli
Biomolecules 2025, 15(8), 1064; https://doi.org/10.3390/biom15081064 - 23 Jul 2025
Viewed by 313
Abstract
Intimal hyperplasia (IH) compromises the patency of arteriovenous fistula (AVF) vascular access in patients with end-stage kidney disease. Uncontrolled cell proliferation and migration, driven by inflammation, shear stress and surgery, are well-known triggers in IH. Recently, microRNAs (miRNAs) have emerged as regulators of [...] Read more.
Intimal hyperplasia (IH) compromises the patency of arteriovenous fistula (AVF) vascular access in patients with end-stage kidney disease. Uncontrolled cell proliferation and migration, driven by inflammation, shear stress and surgery, are well-known triggers in IH. Recently, microRNAs (miRNAs) have emerged as regulators of core mechanisms in cardiovascular diseases and as potential markers of IH. This study was aimed at identifying a specific miRNA panel in failed AVFs and clarifying the miRNA involvement in IH. miRNA profiling performed in tissues from patients with IH (AVFs) and normal veins (NVs) highlighted a subset of four miRNAs significantly deregulated (hsa-miR-155-5p, hsa-miR-449a-5p, hsa-miR-29c-3p, hsa-miR-194-5p) between the two groups. These miRNAs were analyzed in tissue-derived cells (NVCs and AVFCs), human aortic smooth muscle cells (HAOSMCs) and human umbilical vein endothelial cells (HUVECs). The panel of hsa-miR-449a-5p, hsa-miR-155-5p, hsa-miR-29c-3p and hsa-miR-194-5p was up-regulated in AVFCs, HAOSMCs and HUVEC under inflammatory stimuli. Notably, overexpression of hsa-miR-449a-5p exacerbated the proliferative, migratory and inflammatory features of AVFCs. In vitro pharmacological modulation of these miRNAs with pioglitazone, particularly the down-regulation of hsa-miR-155-5p and hsa-miR-29c-3p, suggested their involvement in IH pathogenesis and a potential translational application. Overall, these findings provide new insights into the pathogenesis of AVF failure, reinforcing the miRNA contribution to IH detection and prevention. Full article
(This article belongs to the Section Molecular Biology)
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14 pages, 8113 KiB  
Article
Cellular and Matrix Organisation of the Human Aortic Valve Interleaflet Triangles
by Najma Latif, Padmini Sarathchandra, Albaraa Al-Holy, Sanida Vaz, Adrian H. Chester and Magdi H. Yacoub
Biology 2025, 14(7), 863; https://doi.org/10.3390/biology14070863 - 16 Jul 2025
Viewed by 200
Abstract
(1) Background: The sophisticated function of the aortic root relies on the coordinated movement of its constituent components. This study examines the extracellular components of the interleaflet triangles (ILTs) and characterises the cells that are present within this region of the aortic root. [...] Read more.
(1) Background: The sophisticated function of the aortic root relies on the coordinated movement of its constituent components. This study examines the extracellular components of the interleaflet triangles (ILTs) and characterises the cells that are present within this region of the aortic root. (2) Methods: A total of 10 human aortic valves and 6 porcine aortic valves were processed for immunohistochemical staining, scanning, and transmission electron microscopy. (3) Results: The three ILTs differed in size and macroscopic appearance. Each triangle comprised up to five distinct layers of tissue: an innermost endothelial layer, an inner elastin-rich layer, a thicker outer layer comprising densely packed layers of collagen and glycosaminoglycans, and an outer layer of intermingled myocardial and adipose tissue. A band of cells near the luminal surfaces of all ILTs expressed smooth muscle cell α-actin with variable expression of smooth muscle myosin heavy chain. In all the ILTs, there was evidence of neurofilament staining, indicating the presence of nerve fibres. (4) Conclusions: Each ILT is unique in its structure and organisation, with differing amounts of elastin and collagen, as well as myocardial, adipose, and fibrous content. The ILTs contain multiple cell types in varying abundance. Functional studies are required to determine the role of the different cells and their organisation in contributing to the sophisticated, dynamic behaviour of the aortic root. Full article
(This article belongs to the Section Cell Biology)
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20 pages, 10334 KiB  
Article
Negative Air Ions Attenuate Nicotine-Induced Vascular Endothelial Dysfunction by Suppressing AP1-Mediated FN1 and SPP1
by Sha Xiao, Tianjing Wei, Mingyang Xiao, Mingming Shan, Ziqi An, Na Li, Jing Zhou, Shuang Zhao and Xiaobo Lu
Antioxidants 2025, 14(7), 859; https://doi.org/10.3390/antiox14070859 - 14 Jul 2025
Viewed by 353
Abstract
Nicotine-induced oxidative stress contributes significantly to vascular endothelial dysfunction. While negative air ions (NAIs) demonstrate potential blood-pressure-regulating and antioxidant properties, their mechanistic role remains unclear. This study examined the effects of NAIs against nicotine-induced oxidative damage and vascular endothelial injury in spontaneously hypertensive [...] Read more.
Nicotine-induced oxidative stress contributes significantly to vascular endothelial dysfunction. While negative air ions (NAIs) demonstrate potential blood-pressure-regulating and antioxidant properties, their mechanistic role remains unclear. This study examined the effects of NAIs against nicotine-induced oxidative damage and vascular endothelial injury in spontaneously hypertensive rats (SHRs). Western blotting was used to detect the expression levels of the α7nAChR/MAPK/AP1 pathway. Transcriptomic sequencing was performed to identify the differentially expressed genes after treatment with nicotine or NAIs. Furthermore, reactive oxygen species (ROS), endothelin-1 (ET-1), and [Ca2+]i levels were detected in human aortic endothelial cells (HAECs) treated with nicotine, and the relationship between transcription factor activator protein 1 (AP1) and the target genes was further elucidated through ChIP–qPCR. Nicotine exposure in SHRs elevated blood pressure and induced oxidative damage through α7nAChR/MAPK/AP1 pathway activation, causing endothelial structural disruption. These effects manifested as decreased NO/eNOS and increased ET-1/ETab expression, while these changes were reversed by NAIs. In HAECs, nicotine impaired proliferation while increasing oxidative stress and [Ca2+]i levels. This endothelial damage was markedly attenuated by either NAIs or fibronectin 1 (Fn1)/secreted phosphoprotein 1 (Spp1) knockdown. Mechanistically, we identified AP1 as the transcriptional regulator of FN1 and SPP1. NAIs attenuate nicotine-induced endothelial dysfunction in hypertension by inhibiting AP1-mediated FN1 and SPP1 activation, providing novel insights for smoking-associated cardiovascular risk. Full article
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17 pages, 5511 KiB  
Article
Distinct Roles of apoE Receptor-2 Cytoplasmic Domain Splice Variants in Cardiometabolic Disease Modulation
by Anja Jaeschke, April Haller and David Y. Hui
Biomedicines 2025, 13(7), 1692; https://doi.org/10.3390/biomedicines13071692 - 10 Jul 2025
Viewed by 369
Abstract
Background/Objectives: Apolipoprotein E receptor-2 (apoER2) exists in various alternatively spliced forms, including variants that express apoER2 with or without exon 19 in the cytoplasmic domain. This study compared vascular response to endothelial denudation, as well as diet-induced atherosclerotic and metabolic diseases, between [...] Read more.
Background/Objectives: Apolipoprotein E receptor-2 (apoER2) exists in various alternatively spliced forms, including variants that express apoER2 with or without exon 19 in the cytoplasmic domain. This study compared vascular response to endothelial denudation, as well as diet-induced atherosclerotic and metabolic diseases, between genetically modified mice that exclusively expressed the apoER2 splice variant with or without exon 19 to determine the impact of apoER2 exon 19 motif in cardiometabolic disease modulation. Methods: Vascular response to injury was assessed by measuring neointima area of the carotid arteries after endothelial denudation. The genetically modified mice were also fed a high-fat high-cholesterol diet for 16 weeks for the determination of body weight gain, glucose and insulin levels, glucose tolerance and insulin secretion. Additionally, adipose tissue inflammation was assessed by analysis of adipose gene expression, and atherosclerosis was characterized by measuring fatty lesion size in the whole aorta, as well as in the aortic roots. Results: The results showed that whereas the expression of either splice variant is sufficient to impede denudation-induced fibrotic neointima formation and complex necrotic atherosclerotic lesions, the expression of the apoER2 splice variant containing exon 19 is necessary for the complete protection of injury-induced neointima formation in the vessel wall. However, exclusive expression of either apoER2 cytoplasmic splice variant does not influence the early phase of atherogenesis. Additionally, the exclusive expression of apoER2 without exon 19 promotes adipocyte inflammation and accelerates diet-induced insulin resistance and glucose intolerance. Conclusions: These results indicate that the apoER2 cytoplasmic variants have distinct and cell type-specific roles in influencing cardiometabolic disease development. Full article
(This article belongs to the Special Issue Molecular and Cellular Research in Diabetes and Metabolic Diseases)
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15 pages, 1404 KiB  
Review
Aortic Valve Defect as an Independent Risk Factor for Endothelial Dysfunction
by Mateusz Malina, Waldemar Banasiak and Adrian Doroszko
Cells 2025, 14(12), 885; https://doi.org/10.3390/cells14120885 - 11 Jun 2025
Viewed by 564
Abstract
Endothelial dysfunction (ED) has been identified as a precursor to micro- and macroangiopathic complications and an independent risk factor for major adverse cardiac events (MACEs). Recent studies have identified a novel risk factor for ED: severe aortic stenosis (AS). Traditionally linked to other [...] Read more.
Endothelial dysfunction (ED) has been identified as a precursor to micro- and macroangiopathic complications and an independent risk factor for major adverse cardiac events (MACEs). Recent studies have identified a novel risk factor for ED: severe aortic stenosis (AS). Traditionally linked to other established risk factors for endothelial cell dysregulation, AS has emerged as a contributor to ED, which is supported by the improvement of endothelial function following transcatheter (TAVR) or surgical (SAVR) interventions. Furthermore, the observation of ED in patients with a dysfunctional bicuspid aortic valve (BAV) at a younger age suggests a distinct impact of AS on ED. A promising hypothesis is a hemodynamic theory suggesting that changes in the shear stress of the ascending aortic wall and peripheral vessels, along with subclinical hemolysis caused by turbulent blood flow, could lead to reduced nitric oxide (NO) bioavailability. Current hypotheses on ED have yet to consider the influence of concomitant aortic stenosis in BAV. Additionally, studies examining potential intravascular hemolysis in BAV patients or the impact of surgical treatment of this defect on endothelial function are scarce. The aim of this review is to summarize the current knowledge on the mechanisms underlying ED in patients with AS or BAV and to identify possible directions for future research. Full article
(This article belongs to the Special Issue Novel Insight into Endothelial Function and Atherosclerosis)
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24 pages, 6482 KiB  
Article
Transmembrane Protein-184A Interacts with Syndecan-4 and Rab GTPases and Is Required to Maintain VE-Cadherin Levels
by Leanna M. Altenburg, Stephanie H. Wang, Grace O. Ciabattoni, Amelia Kennedy, Rachel L. O’Toole, Sara L. N. Farwell, M. Kathryn Iovine and Linda J. Lowe-Krentz
Cells 2025, 14(11), 833; https://doi.org/10.3390/cells14110833 - 3 Jun 2025
Viewed by 762
Abstract
VE-cadherin (VE-cad) membrane stability and localization regulates adhesion formation and actin cytoskeleton dynamics in angiogenesis and vascular remodeling and requires the heparan sulfate proteoglycan (HSPG), Syndecan-4 (Sdc4). This study characterizes the interactions of the heparin receptor, Transmembrane protein-184A (TMEM184A), and Sdc4 in bovine [...] Read more.
VE-cadherin (VE-cad) membrane stability and localization regulates adhesion formation and actin cytoskeleton dynamics in angiogenesis and vascular remodeling and requires the heparan sulfate proteoglycan (HSPG), Syndecan-4 (Sdc4). This study characterizes the interactions of the heparin receptor, Transmembrane protein-184A (TMEM184A), and Sdc4 in bovine aortic endothelial cells (BAOECs) and the regenerating Zebrafish (ZF) caudal fin and measures the effect of siRNA TMEM184A KD (siTMEM) and TMEM184A overexpression (TMEM OE) on VE-cad levels and localization in confluent and sub-confluent cultured BAOECs. Additionally, we examined the effect of siTMEM on key Rab GTPase trafficking regulators and migrating BAOECs in scratch wound healing assays. We demonstrated that TMEM184A and Sdc4 colocalize in BAOECs and that Sdc4 OE increases colocalization in an HS chain dependent manner, while both Tmem184a and Sdc4 cooperate synergistically in ZF fin angiogenic and tissue repair. We also showed that siTMEM decreases VE-cad membrane and cytoplasmic levels, while increasing scratch wound migration rates. However, TMEM OE cells show increased vesicle formation and VE-cad trafficking and membrane recovery. These findings characterize TMEM184A-Sdc4 cooperation in angiogenesis and indicate a dual function of TMEM184A in signaling and trafficking in vascular cells that promotes VE-cad recovery and membrane localization. Full article
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15 pages, 263 KiB  
Article
Biomarkers of Calcification, Endothelial Injury, and Platelet-Endothelial Interaction in Patients with Aortic Valve Stenosis
by Paweł Bańka, Klaudia Męcka, Adrianna Berger-Kucza, Karolina Wrona-Kolasa, Anna Rybicka-Musialik, Beata Nowak, Marek Elżbieciak, Magdalena Mizia-Szubryt, Wojciech Wróbel, Tomasz Francuz, Michał Lelek, Agnieszka Kosowska, Wojciech Garczorz, Tomasz Bochenek, Andrzej Swinarew, Jarosław Paluch, Maciej Wybraniec and Katarzyna Mizia-Stec
Int. J. Mol. Sci. 2025, 26(10), 4873; https://doi.org/10.3390/ijms26104873 - 19 May 2025
Viewed by 571
Abstract
Aortic stenosis (AS) is a progressive valvular heart disease characterized by fibrocalcific remodeling, inflammation, and hemodynamic disturbances. Serum biomarkers may indirectly reflect these processes. Autotaxin (ATX) and lysophosphatidic acid (LPA) have been implicated in osteogenic differentiation of valvular interstitial cells, while growth differentiation [...] Read more.
Aortic stenosis (AS) is a progressive valvular heart disease characterized by fibrocalcific remodeling, inflammation, and hemodynamic disturbances. Serum biomarkers may indirectly reflect these processes. Autotaxin (ATX) and lysophosphatidic acid (LPA) have been implicated in osteogenic differentiation of valvular interstitial cells, while growth differentiation factor-15 (GDF-15) reflects cellular stress and vascular changes. Thrombomodulin (TM) indicates endothelial injury and interacts with thrombin. This study aimed to evaluate biomarkers focusing on serum ATX, LPA, GDF-15, and TM levels and flow-mediated dilatation (FMD) in patients with AS. Overall, 149 patients were included in the study: 86 consecutive patients with AS hospitalized due to qualification for invasive treatment of AS and 63 controls. The clinical characteristics, echocardiographic data, FMD, and the following biomarkers—ATX, LPA, GDF-15, and TM—were included in the analysis. AS patients presented increased serum levels of ATX, GDF-15, and TM as compared to the controls. Differences in LPA levels were not statistically significant. FMD values were significantly lower in AS patients. The biomarkers mentioned above and FMD correlated with AS severity. There were no differences in both biomarkers’ serum levels and FMD regarding the hemodynamic AS phenotype. GDF-15 serum level was a risk factor for all-cause mortality and MACCE in the 12-month follow-up. Full article
(This article belongs to the Special Issue Cardiovascular Diseases: From Pathology to Therapeutics)
14 pages, 1536 KiB  
Article
Secreted Protein Acidic and Rich in Cysteine (SPARC) Induced by the Renin–Angiotensin System Causes Endothelial Inflammation in the Early Stages of Hypertensive Vascular Injury
by Hiroe Toba, Mitsushi J. Ikemoto, Miyuki Kobara, Denan Jin, Shinji Takai and Tetsuo Nakata
Int. J. Mol. Sci. 2025, 26(9), 4414; https://doi.org/10.3390/ijms26094414 - 6 May 2025
Viewed by 600
Abstract
Secreted protein acidic rich in cysteine (SPARC), one of the extracellular matrix proteins, is highly induced during inflammation. We investigated the pathophysiological regulation and role of SPARC in vascular inflammation in a rat model of hypertension created using deoxycorticosterone acetate (DOCA, 40 mg/kg/week, [...] Read more.
Secreted protein acidic rich in cysteine (SPARC), one of the extracellular matrix proteins, is highly induced during inflammation. We investigated the pathophysiological regulation and role of SPARC in vascular inflammation in a rat model of hypertension created using deoxycorticosterone acetate (DOCA, 40 mg/kg/week, s.c.) and salt (1% in drinking water). DOCA–salt administration time-dependently increased systolic blood pressure during the 3-week treatment period, blunted endothelium-dependent vasodilation, and increased monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in the aorta. SPARC expression transiently increased until week 2 in the DOCA–salt rat aorta. Interestingly, aortic SPARC levels correlated with blood pressure and the levels of MCP-1 and LOX-1 during 0–2 weeks. The AT1 receptor blocker, losartan, suppressed the overexpression of SPARC, and in vitro treatment with angiotensin II enhanced the production of SPARC in rat aortic endothelial cells. Exposure to recombinant SPARC protein induced overexpression of MCP-1 and LOX-1 mRNA in endothelial cells. Bioactive forms of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), excessive activation of which contributes to pathological states and overexpression of which is reported to be induced by SPARC, were increased in the DOCA–salt rat aorta. These results suggest that SPARC is induced by the vascular renin–angiotensin system and causes inflammation in the early stages of hypertensive vascular injury, and that activation of ADAMTS1 might be related to the proinflammatory effects of SPARC. Full article
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19 pages, 17036 KiB  
Article
The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis”
by Christian Freise, Susanne Metzkow, Andreas Zappe, Monika Ebert, Nicola Stolzenburg, Julia Hahndorf, Jörg Schnorr, Kevin Pagel and Matthias Taupitz
Toxins 2025, 17(5), 217; https://doi.org/10.3390/toxins17050217 - 25 Apr 2025
Viewed by 743
Abstract
Gut-derived uremic toxins (UTs) contribute to cardiovascular disorders like atherosclerosis and cardiomyopathy in patients with chronic kidney disease (CKD), causing increased cardiovascular morbidity and mortality. The intermediate steps between higher concentrations of gut-derived UTs and organ damage caused by UTs are still insufficiently [...] Read more.
Gut-derived uremic toxins (UTs) contribute to cardiovascular disorders like atherosclerosis and cardiomyopathy in patients with chronic kidney disease (CKD), causing increased cardiovascular morbidity and mortality. The intermediate steps between higher concentrations of gut-derived UTs and organ damage caused by UTs are still insufficiently understood. Glycosaminoglycans (GAGs) as components of the extracellular matrix are known to interact with various ligands such as growth factors or receptors, thereby influencing (patho)physiological processes. We previously found that the UT inorganic phosphate (Pi) induces the synthesis and sulphation of the GAGs heparan sulphate and chondroitin sulphate in the rat vascular smooth muscle cell (VSMC) line A7r5 and in the human endothelial cell (EC) line EA.Hy926. The aim of this study was to investigate if other organic UTs modulate GAGs in vascular cells as well. We treated ex vivo cultures of rat aortic rings as well as primary rat VSMCs and human ECs with the UTs Pi, indoxylsulphate (IS), p-cresylsulphate (pCS), trimethylamine N-oxide (TMAO), and urea, and analyzed the samples by histological staining, qPCR, western blot, HPLC, and colorimetric assays. The UT treatment of aortic rings and cells increased contents of sulphated GAGs and hyaluronic acid. UT-treated cells contained higher amounts of 4S- and 6S-sulphated GAGs compared to controls. This was accompanied by altered expressions of genes and proteins relevant for GAG metabolism. Mechanistically, the effects of the UTs on GAGs involve the activation of the PI3K/Akt pathway and of the transcription factor NF-κB. In conclusion, the UT-induced remodeling of the cardiovascular matrix by upregulation of sulphated GAGs and hyaluronic acid in aortic tissue and vascular cells might be a missing link between gut-derived UT and pathophysiological alterations in the cardiovascular system in the sense of a gut–matrix axis. Full article
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17 pages, 3065 KiB  
Article
In Vitro Study of Vitamin D Effects on Immune, Endothelial, and Vascular Smooth Muscle Cells in Chronic Kidney Disease
by Kajal Kamboj, Vivek Kumar and Ashok Kumar Yadav
Int. J. Mol. Sci. 2025, 26(9), 3967; https://doi.org/10.3390/ijms26093967 - 23 Apr 2025
Viewed by 694
Abstract
Vitamin D has been shown to improve immunity as well as vascular function. We investigated the effect of cholecalciferol on T-cell phenotype in cultured peripheral blood mononuclear cells (PBMCs) from twenty vitamin D-deficient, non-diabetic chronic kidney disease (CKD) subjects. We also studied vitamin [...] Read more.
Vitamin D has been shown to improve immunity as well as vascular function. We investigated the effect of cholecalciferol on T-cell phenotype in cultured peripheral blood mononuclear cells (PBMCs) from twenty vitamin D-deficient, non-diabetic chronic kidney disease (CKD) subjects. We also studied vitamin D effects on endothelial and vascular function markers in human aortic endothelial cells (HAECs) and in human aortic smooth muscle cells (HASMCs), respectively. We studied endothelial nitric oxide synthase (eNOS), mitogen-activated protein kinase 38 (p38 Map kinase), protein kinase B (Akt), and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) in HAECs and α-smooth muscle actin (α-SMA), smooth muscle calponin (SM-Calponin), smooth muscle myosin heavy chain (SM-MHC), and calcium-sensing receptor (CaSR) in HASMCs. Vitamin D receptors (VDRs) and CYP27B1 were studied in both cell types. In cultured PBMCs isolated from CKD subjects, the percentage of T helper 1(TH1) cells significantly decreased while that of T helper 2 (TH2) cells increased after cholecalciferol treatment. No significant change in intracellular and surface markers of T helper 17 (TH17) and T regulatory (Treg) cells was observed. In vitro treatment of HASMCs and HAECs with cholecalciferol led to significant and favorable alterations in mRNA expression of markers of vascular smooth muscle cells, i.e., α-SMA, SM-Calponin, and SM-MHC. Regarding endothelial cell markers, mRNA encoding eNOS, p38 Map kinase, protein kinase B (Akt), NADPH oxidase, VDR, and CYP27B1 were also significantly changed. Finally, the expression levels of the following proteins were notably altered: NADPH oxidase and protein kinase B (Akt) (in HAECs); SM-MHC and SM-Calponin (in HASMCs). In vitro treatment of PBMCs with cholecalciferol led to a favorable change in T-cell population, decreasing TH1 and increasing TH2 cell percentage, along with beneficial alterations in mRNA expression of HASMCs and HAECs’ cell markers. This study provides evidence that cholecalciferol can influence immune and vascular function in CKD. Full article
(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)
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16 pages, 1521 KiB  
Perspective
Origins of Aortic Coarctation: A Vascular Smooth Muscle Compartment Boundary Model
by Christina L. Greene, Geoffrey Traeger, Akshay Venkatesh, David Han and Mark W. Majesky
J. Dev. Biol. 2025, 13(2), 13; https://doi.org/10.3390/jdb13020013 - 18 Apr 2025
Viewed by 1886
Abstract
Compartment boundaries divide the embryo into segments with distinct fates and functions. In the vascular system, compartment boundaries organize endothelial cells into arteries, capillaries, and veins that are the fundamental units of a circulatory network. For vascular smooth muscle cells (SMCs), such boundaries [...] Read more.
Compartment boundaries divide the embryo into segments with distinct fates and functions. In the vascular system, compartment boundaries organize endothelial cells into arteries, capillaries, and veins that are the fundamental units of a circulatory network. For vascular smooth muscle cells (SMCs), such boundaries produce mosaic patterns of investment based on embryonic origins with important implications for the non-uniform distribution of vascular disease later in life. The morphogenesis of blood vessels requires vascular cell movements within compartments as highly-sensitive responses to changes in fluid flow shear stress and wall strain. These movements underline the remodeling of primitive plexuses, expansion of lumen diameters, regression of unused vessels, and building of multilayered artery walls. Although the loss of endothelial compartment boundaries can produce arterial–venous malformations, little is known about the consequences of mislocalization or the failure to form SMC-origin-specific boundaries during vascular development. We propose that the failure to establish a normal compartment boundary between cardiac neural-crest-derived SMCs of the 6th pharyngeal arch artery (future ductus arteriosus) and paraxial-mesoderm-derived SMCs of the dorsal aorta in mid-gestation embryos leads to aortic coarctation observed at birth. This model raises new questions about the effects of fluid flow dynamics on SMC investment and the formation of SMC compartment borders during pharyngeal arch artery remodeling and vascular development. Full article
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14 pages, 1489 KiB  
Review
Epigenetic Biomarkers in Thoracic Aortic Aneurysm, Dissection, and Bicuspid Aortopathy: A Comprehensive Review
by Dimitrios E. Magouliotis, Serge Sicouri, Noah Sicouri, Massimo Baudo, Francesco Cabrucci, Yoshiyuki Yamashita and Basel Ramlawi
Biomolecules 2025, 15(4), 568; https://doi.org/10.3390/biom15040568 - 11 Apr 2025
Viewed by 962
Abstract
Thoracic aortic disease (TAD) encompasses a spectrum of life-threatening conditions, including thoracic aortic aneurysm (TAA), acute type A aortic dissection (ATAAD), and bicuspid aortic valve (BAV)-associated aortopathy. While genetic mutations are well-documented contributors, emerging evidence highlights epigenetic mechanisms as critical regulators of TAD [...] Read more.
Thoracic aortic disease (TAD) encompasses a spectrum of life-threatening conditions, including thoracic aortic aneurysm (TAA), acute type A aortic dissection (ATAAD), and bicuspid aortic valve (BAV)-associated aortopathy. While genetic mutations are well-documented contributors, emerging evidence highlights epigenetic mechanisms as critical regulators of TAD pathogenesis. This comprehensive review explores the role of epigenetic modifications—DNA methylation, histone modifications, and microRNA (miRNA) regulation—in vascular remodeling, extracellular matrix degradation, and endothelial dysfunction. Aberrant DNA methylation patterns have been implicated in TAA and ATAAD, influencing genes responsible for vascular integrity and inflammation. Histone modifications modulate smooth muscle cell phenotype switching, impacting aneurysm progression. Additionally, dysregulated miRNA expression contributes to endothelial barrier disruption and extracellular matrix remodeling, presenting novel avenues for biomarker discovery. The reversibility of epigenetic modifications offers a promising therapeutic target, with pharmacological agents such as histone deacetylase inhibitors and miRNA-based therapies showing potential in preclinical models. This review underscores the translational potential of epigenetic biomarkers for early disease detection, risk stratification, and precision medicine approaches. Further research is needed to integrate these findings into clinical practice, paving the way for innovative diagnostic and therapeutic strategies in TAD management. Full article
(This article belongs to the Section Molecular Biomarkers)
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15 pages, 3066 KiB  
Article
Vasodilatory Effect of n-Butanol Extract from Sanguisorba officinalis L. and Its Mechanism
by Hangyu Jin, Jiaze Li, Shuyuan Wang, Enyi Jin, Jun Zhe Min, Gao Li, Yun Jung Lee and Lihua Cao
Plants 2025, 14(7), 1095; https://doi.org/10.3390/plants14071095 - 1 Apr 2025
Viewed by 567
Abstract
The dried root of Sanguisorba officinalis L. (commonly known as Diyu) has been studied for its various pharmacological effects, including its antibacterial, antitumor, antioxidant, and anti-inflammatory activities. In the present study, primary cultured vascular endothelial cells (HUVECs) and isolated phenylephrine-precontracted rat thoracic aortic [...] Read more.
The dried root of Sanguisorba officinalis L. (commonly known as Diyu) has been studied for its various pharmacological effects, including its antibacterial, antitumor, antioxidant, and anti-inflammatory activities. In the present study, primary cultured vascular endothelial cells (HUVECs) and isolated phenylephrine-precontracted rat thoracic aortic rings were examined to investigate the possible mechanism of a butanol extract of Diyu (BSO) in its vascular relaxant effect. HUVECs treated with BSO produced a significantly higher amount of nitric oxide (NO) compared to the control. However, its production was inhibited by pretreatment with NG-nitro-L-arginine methylester (L-NAME) or wortmannin. BSO also increased the phosphorylation levels of endothelial nitric oxide synthase (eNOS) and Akt. In the aortic ring, BSO relaxed PE-precontracted rat thoracic aortic rings in a concentration-dependent manner. The absence of the vascular endothelium significantly attenuated BSO-induced vasorelaxation. The non-selective NOS inhibitor, L-NAME, and the selective inhibitor of soluble guanylyl cyclase (sGC), 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ), dramatically inhibited the BSO-induced relaxation effect of the endothelium-intact aortic ring. Ca2+-free buffer and intracellular Ca2+ homeostasis regulators (TG, Gd3+, and 2–APB) inhibited BSO-induced vasorelaxation. In Ca2+-free Krebs solution, BSO markedly reduced PE-induced contraction. Vasodilation induced by BSO was significantly inhibited by wortmannin, an inhibitor of Akt. Pretreatment with the non-selective inhibitor of Ca2+-activated K+ channels (KCa), tetraethylammonium (TEA), significantly attenuated the BSO-induced vasorelaxant effect. Furthermore, BSO decreased the systolic blood pressure and heart rate in a concentration-dependent manner in rats. In conclusion, BSO induces vasorelaxation via endothelium-dependent signaling, primarily through the activation of the PI3K-Akt-eNOS-NO signaling pathway in endothelial cells, and the activation of the NO-sGC-cGMP-K⁺ channels pathway in vascular smooth muscle cells. Additionally, store-operated Ca2+ entry (SOCE)-eNOS pathways and the inhibition of Ca2⁺ mobilization from intracellular stores contribute to BSO-induced vasorelaxation. Full article
(This article belongs to the Special Issue Ethnobotanical and Pharmacological Study of Medicinal Plants)
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14 pages, 4588 KiB  
Article
The Marine Compound Isaridin E Ameliorates Lipopolysaccharide-Induced Vascular Endothelial Inflammation via the Downregulation of the TLR4/NF-κB Signaling Pathway
by Jing Liu, Xin Zeng, Yu-Quan Lin, Yu-Sheng Peng, Lan Liu, Sen-Hua Chen and Yan-Hua Du
Mar. Drugs 2025, 23(4), 145; https://doi.org/10.3390/md23040145 - 28 Mar 2025
Viewed by 632
Abstract
Isaridin E, a cyclodepsipeptide derived from the marine fungus Beauveria felina (SYSU-MS7908), has been demonstrated to possess multiple biological properties. In this study, we employed both lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) and a LPS-induced murine endotoxemia model to investigate its [...] Read more.
Isaridin E, a cyclodepsipeptide derived from the marine fungus Beauveria felina (SYSU-MS7908), has been demonstrated to possess multiple biological properties. In this study, we employed both lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) and a LPS-induced murine endotoxemia model to investigate its anti-inflammatory effects. Our results revealed that isaridin E suppressed the expression of pro-inflammatory cytokines and adhesion molecules in a concentration dependent manner, while also reducing monocyte adhesion to endothelial cells. Furthermore, this compound attenuated vascular hyperpermeability and inflammatory cell infiltration in the lungs, as well as preserving the integrity of the aortic and pulmonary tissues. At the molecular level, isaridin E was found to downregulate TLR4 expression, increase IκBα levels, and inhibit the LPS-induced phosphorylation and nuclear translocation of NF-κB p65. In conclusion, our findings indicate that isaridin E exerts robust anti-inflammatory effects in LPS-induced endotoxemia through the suppression of the TLR4/NF-κB signaling axis, positioning it as a promising therapeutic candidate for vascular inflammatory disorders. Full article
(This article belongs to the Special Issue Marine Anti-inflammatory Agents )
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14 pages, 2999 KiB  
Article
Downregulated Expression of miR-200c-3p in Plasma Exosome as a Potential Biomarker in Takayasu’s Arteritis
by Lihong Du, Chenglong Fang, Biqing Huang, Xiaofeng Zeng, Jing Li and Xinping Tian
Int. J. Mol. Sci. 2025, 26(7), 2881; https://doi.org/10.3390/ijms26072881 - 22 Mar 2025
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Abstract
Our previous work identified several differentially expressed miRNAs (DEmiRNAs) in plasma exosomes from Takayasu’s arteritis (TAK) patients. This study aimed to validate these findings and explore the correlation between DEmiRNAs and clinical parameters in untreated TAK. Plasma exosomes were isolated from 30 untreated [...] Read more.
Our previous work identified several differentially expressed miRNAs (DEmiRNAs) in plasma exosomes from Takayasu’s arteritis (TAK) patients. This study aimed to validate these findings and explore the correlation between DEmiRNAs and clinical parameters in untreated TAK. Plasma exosomes were isolated from 30 untreated TAK patients and 20 healthy controls. qPCR was used to quantify miR-34a-5p, miR-143-3p, miR-22-3p, miR-200c-3p, and miR-21-5p expression. Correlations between miRNA levels, clinical data, inflammation markers, and T helper cell frequencies were analyzed. The target genes of validated DEmiRNAs were identified using mirDIP, and pathway enrichment analysis was performed using GO/KEGG. The effect of validated DEmiRNAs on the MAPK pathway and proliferation in human aortic endothelial cells (HAECs) was investigated in vitro. Only miR-200c-3p expression was validated as significantly downregulated in plasma exosomes from untreated TAK patients. Lower miR-200c-3p levels correlated negatively with ITAS-2010 scores and were associated with relapsed disease. MiR-200c-3p levels also negatively correlated with circulating Th17.1 cell frequencies. In vitro, the TAK exosome treatment activated ERK1/2 and JNK pathways and promoted HAEC proliferation, which was inhibited by the miR-200c-3p mimic. The pathway enrichment analysis showed that the MAPK pathway may be involved. This study confirms the reduced miR-200c-3p expression in plasma exosomes from TAK patients, suggesting its potential as a biomarker for vascular inflammation. MiR-200c-3p may exert protective effects in TAK by suppressing MAPK pathway activation and EC proliferation. Full article
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