Search Results (2,341)

Reptiles with diving capabilities have evolved physiological adaptations as well as conformational changes to temporarily sustain life underwater. Despite the importance of both respiratory and cardiovascular systems during diving, most studies have focused on respiratory adaptations. Thus, characterisation of previously undescribed cardiovascular anatomical variations in diving vertebrates is of broad interest. Thirteen clinically healthy, free-ranging adult female Murray River turtles (Chelidae: Emydura macquarii) were collected for research purposes, euthanised and autopsied. Prominent, valve-like structures, comprised exclusively of smooth muscle myocytes, were identified in medium- and large-calibre muscular arteries of all individuals. Additionally, multiple intramural vascular channels, mimicking post-thrombotic recanalization, were observed within medium-calibre muscular arteries. Further, we confirmed the presence of alpha-smooth-muscle actin-positive cells lining the cardiac atria in E. macquarii. Quantitative morphometric analyses demonstrated that the valve-like structures frequently occupied a substantial proportion of the vascular lumen, in some cases exceeding 90% luminal narrowing. Their consistent presence across multiple individuals and organ systems supports the interpretation that these are physiological vascular structures rather than artefacts. This study examines the potential physiological and evolutionary roles of these vascular structures, providing a basis for further research into cardiovascular adaptations in vertebrates subjected to postural changes and diving-related haemodynamic challenges. Full article

Heritable thoracic aortic diseases (HTAD) are inherited conditions that increase the risk of thoracic aortic aneurysms, dissections, and premature aortic rupture. Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based view involving extracellular matrix (ECM) architecture, transforming growth factor-β (TGFβ) signaling, and vascular smooth muscle cell contractility. Marfan syndrome, Loeys–Dietz syndrome, and nonsyndromic HTAD demonstrate how genetic mutations can disrupt the components that stabilize the aortic wall. These pathogenic mechanisms influence matrix organization, intracellular signaling, and the contractile machinery within the mechanically stressed proximal aorta. In this review, we summarize current mechanistic insights into the major forms of HTAD and discuss how new molecular and cellular concepts could influence surveillance, genetic counseling, and genotype-guided therapeutic strategies. Full article

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by vascular smooth muscle cell (VSMC) dysfunction and disrupted calcium homeostasis. While transient receptor potential canonical 6 (TRPC6) and transient receptor potential canonical 1 (TRPC1) are known to mediate receptor-operated calcium entry (ROCE) and store-operated calcium entry (SOCE), respectively, the specific contributions of SOCE and ROCE to AAA pathogenesis, and the regulatory interaction between transient receptor potential melastatin 8 (TRPM8) and TRPC1 remain unexplored. In this study, we analyzed human AAA tissues, a papain-induced mouse model, and angiotensin II (Ang II)-treated human aortic smooth muscle cells using histology, wire myography, calcium imaging, and patch-clamp electrophysiology. We observed significant upregulation of TRPM8, TRPC1, and TRPC6 in both human and experimental AAA, with TRPC1 identified as a key mediator of SOCE under pathological conditions. Pharmacological activation of TRPM8 by menthol attenuated TRPC1-mediated SOCE and associated vasoconstriction, effects that were partially reversed by the TRPM8 antagonist A-2. In Ang II-treated cells, TRPM8 activation reduced SOCE and store-operated calcium currents (I_SOCC), effects that were largely abolished by TRPC1 knockdown. These findings suggest that TRPM8 may limit excessive calcium ion (Ca²⁺) influx and vascular remodeling in AAA, pointing to a potential endogenous mechanism to counteract maladaptive calcium signaling in AAA progression. Full article

Coronary artery bypass grafting (CABG) using the autologous saphenous vein (SV) remains widely performed for obstructive atherosclerosis; however, vein graft disease drives recurrent ischaemia through early thrombosis and progressive intimal hyperplasia, and accelerated atherosclerosis developing within the grafts. Extracellular vesicles (EVs) are membrane-bound particles that transfer proteins, lipids, and microRNAs between cells. They modulate endothelial dysfunction, vascular smooth muscle cell phenotypic switching, inflammation, and coagulation, which are core processes in vein graft remodelling. Arterialisation exposes the vein to abrupt rises in shear stress, cyclic stretch, and intraluminal pressure. These forces increase EV release and reshape EV cargo in experimental systems, suggesting a potential mechanism for amplifying early graft injury which warrants direct investigation in vein tissue. This review synthesises current evidence for cell-specific EV contributions from ECs, vascular smooth muscle cells, platelets, and macrophages, and appraises EV-associated microRNAs with biomarker potential relevant to graft failure pathways. We also review therapeutic strategies that may modulate EV signalling including antiplatelet therapy, statins, KCa3.1 inhibition, and pro-reparative mesenchymal stromal cell-derived EVs. No published clinical studies evaluate EV-based biomarkers specifically for saphenous vein graft patency, and none prospectively predict saphenous graft failure. CABG provides a well-defined time zero event that enables longitudinal sampling and risk stratification. Prospective studies linking EV phenotypes and miRNA signatures to imaging-defined graft outcomes are needed to support clinical translation. Full article

Vascular calcification is a strong predictor of cardiovascular mortality and lacks effective treatment. The transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes is a key driver of calcification. This study identifies a regulatory role for Hyaluronan (HA) in VSMC osteogenic differentiation and arterial calcification. Human aortic VSMCs stimulated with high phosphate and/or pro-inflammatory cytokines (IL6 and TGF-β1) exhibited increased RUNX2, alkaline phosphatase and osteopontin expression, along with reduced contractility and elevated calcium deposition. This corresponded with reduced HA deposition and downregulation of HA synthase enzymes (HAS1, HAS2), Hyaluronidase enzymes (Hyal1), and HA binding proteins (CD44, TSG-6), whilst HAS3 and versican were upregulated. Comparable alterations in HA and protein expression were observed in an in vivo model of arterial calcification using vitamin K-deficient warfarin-fed mice. Pharmacological inhibition of HA synthesis, enzyme-mediated HA degradation and siRNA/plasmid modulation of HAS isoenzymes demonstrated a possible functional link between HA regulation and VSMC osteogenic differentiation. This study establishes HA and its associated binding proteins as key regulators of arterial calcification, highlighting a novel pathway for potential therapeutic intervention. Full article

Moyamoya angiopathy (MMA) is a rare, chronic progressive cerebrovascular condition characterized by bilateral stenosis or occlusion of the terminal internal carotid arteries and their major branches. This progressive occlusion triggers the development of telangiectatic and fragile vessels at the base of the brain, creating the characteristic angiographic appearance of a “puff of smoke.” Depending on the etiology, MMA is classified as Moyamoya Disease (MMD) when idiopathic and primary or Moyamoya Syndrome (MMS) when associated with underlying systemic conditions. While the RNF213 gene, particularly the p.R4810K variant, is recognized as the major susceptibility locus for MMD in East Asian populations, it does not fully account for the global genetic landscape or the phenotypic diversity of the disease. This review provides a comprehensive overview of the genetic architecture of the entire MMA spectrum, exploring loci beyond RNF213. We analyze the role of genes involved in vascular smooth muscle cell contractility (ACTA2, MYH11), TGF-β signaling, and DNA repair mechanisms that drive MMS, alongside the genetic basis of syndromic forms associated with neurofibromatosis type 1, trisomy 21, and RASopathies. Understanding these diverse genetic drivers is crucial for early diagnosis, risk stratification, and the development of targeted molecular therapies. Full article

Myocardial bridging (MB) is a congenital coronary anomaly characterized by systolic compression of the intramyocardial arterial segment and delayed early diastolic artery relaxation, resulting in reduced vessel luminal diameter in diastole. Current evidence suggests that MB, particularly in the left anterior descending artery, may cause anginal symptoms and/or myocardial ischemia through several different pathophysiological and cellular mechanisms acting independently or synergistically: (1) delayed early diastolic relaxation of intramyocardial arterial segment; (2) impaired endothelial-dependent vasodilation with vessel smooth muscle cell hyperactivity in the coronary artery with MB, especially within the bridged segment; (3) focal (septal) ischemia due to “septal steal” phenomenon; and (4) development and progression of an atherosclerotic lesion in the coronary artery segment proximal to MB. Patients with isolated-MB may also experience anginal pain and/or myocardial ischemia due to concomitant structural and/or functional abnormalities of the coronary microcirculation. Both MB and coronary microvascular dysfunction refer to a subgroup of patients with angina and/or ischemia with non-obstructive coronary arteries (ANOCA/INOCA). Therefore, it may be challenging to determine whether MB is causing anginal pain and/or ischemia, particularly since both phenomena have also been reported without MB’s existence. Therefore, comprehensive coronary physiology testing should be encouraged in patients with this coronary anomaly to identify the underlying cause of anginal pain and/or myocardial ischemia, enabling optimal therapeutic strategies in these patients. This review is focused on different pathophysiological and cellular mechanisms of MB-related angina and/or ischemia and future perspectives in the functional assessment of MB severity, bearing in mind the complexity of coronary physiology in the presence of this anomaly. Full article

Preterm labor is a major cause of neonatal morbidity and mortality and is frequently driven by infection-associated inflammation that promotes premature uterine activation. In this study, we investigated the effects of adipose stem cell-derived extracellular vesicles (ASC-EVs) on macrophage-mediated inflammatory signaling in uterine smooth muscle cells (HUtSMCs). An in vitro model was established by treating HUtSMCs with conditioned media derived from LPS-stimulated RAW264.7 macrophages. Activation of signaling pathways was assessed by Western blotting and immunofluorescence, and functional responses were evaluated using calcium flux and collagen gel contraction assays. Conditioned media from LPS-stimulated macrophages induced robust activation of MAPK (ERK1/2 and JNK) and NF-κB signaling, accompanied by IκB degradation and nuclear translocation of phosphorylated p65, whereas ASC-EVs pretreatment significantly attenuated these responses and reduced the expression of pro-inflammatory cytokines, including IL-6, IL-8, and MCP-1. Furthermore, macrophage-conditioned media enhanced intracellular calcium flux and contractile activity in HUtSMCs, both of which were suppressed by ASC-EVs. Inhibition of TLR4 signaling in macrophages reduced the inflammatory potency of conditioned media, indicating a key upstream role of macrophage TLR4 activation. Collectively, these findings demonstrate that ASC-EVs suppress macrophage-mediated inflammatory activation and downstream contractile responses, suggesting their potential as a cell-free therapeutic strategy for preventing inflammation-associated preterm labor. Full article

Vascular calcification is an actively regulated process driven by vascular smooth muscle cell (VSMC) osteogenic reprogramming and promoted by oxidative stress and extracellular matrix remodeling. We investigated whether the novel histone deacetylase inhibitor YAK577 mitigates calcification by modulating an MMP14–NOX2/ROS-associated pathway in calcification medium (CM)-treated VSMCs and a vitamin D₃-induced arterial calcification model in 8-week-old male C57BL/6N mice. Calcification was assessed by Alizarin Red S/von Kossa staining and calcium quantification; osteogenic markers (BMP2, RUNX2, MSX2) and MMPs were examined by qRT-PCR and immunoblotting; intracellular ROS was measured by DHE staining with N-acetylcysteine as an antioxidant control; and MMP14 was manipulated by siRNA knockdown or plasmid overexpression. YAK577 was non-cytotoxic at effective concentrations and reduced CM-induced calcium deposition and osteogenic marker expression. YAK577 reduced MMP14 expression and suppressed CM-induced NOX2/p47phox activation and ROS accumulation, while GSK2795039 attenuated CM-induced DHE fluorescence. MMP14 silencing attenuated, whereas MMP14 overexpression enhanced, osteogenic signaling and increased NOX2. In vivo, YAK577 reduced vitamin D₃-induced aortic calcium burden, histological calcification, and the expression of MMP14, NOX2, and osteogenic markers. These data support a working model in which YAK577 alleviates vascular calcification, at least in part, by suppressing an MMP14-associated NOX2/p47phox–ROS axis. Full article

Background: The pathophysiological mechanisms of Moyamoya angiopathy (MA) are still largely unknown, although a dysfunctional vasculogenesis has been hypothesized to contribute to it. The association between this rare cerebrovascular condition and variants of Ring Finger Protein 213 (RNF213) strengthens the role of genetic factors in MA pathogenesis. Methods: To investigate the molecular mechanisms of MA, we carried out RNA interference (RNAi) targeting RNF213 in human endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). The combined effect of RNAi and/or hypoxia on expression of key angiogenic factors was analyzed through qRT-PCR and Western blot. Functional assays were performed to characterize the impact of RNAi on vasculogenesis. Gene-expression arrays were performed on vessel walls of MA patients and controls. Results: RNF213-RNAi impaired angiogenic capability in ECs, whereas the simultaneous silencing of RNF213 and its phosphatase PTP1B restored angiogenesis function in ECs but worsened it in VSMCs. Angiogenic factor expression appeared to be modulated in ECs by the combined effects of RNAi and/or hypoxia, and in pathological vessels of MA patients as compared with controls. Conclusions: Our findings contribute to associating the relevance of RNF213 in MA cellular models and highlight the importance of EC-VSMC crosstalk for vascular integrity. Additionally, the study could lay the foundations for improving experimental models of MA pathophysiology. Full article

Cardiac fibroblast activation into α-smooth muscle actin (α-SMA)-expressing myofibroblasts is a central event in the progression of cardiac fibrosis. Therapeutic strategies capable of reversing or inhibiting this phenotypic transition are therefore of critical interest. Here, we explore associative changes in transcriptional and post-transcriptional regulators linked to fibroblast activation following atorvastatin exposure in primary human cardiac fibroblasts (HCFs). Atorvastatin treatment (10 µM) was associated with a reduction in α-SMA expression, consistent with decreased myofibroblast activation. This change co-occurred with reduced expression of the transcription factors GATA4 and MEF2C, which are implicated in cardiac cell identity and plasticity. Concurrently, atorvastatin treatment was associated with selective increase in specific fibrosis-related microRNAs, including miR-24, miR-26a, and miR-133a, whereas the expression of miR-21 and miR-23a remained unchanged. Together, these findings describe a coordinated pattern of transcriptional and post-transcriptional changes associated with atorvastatin exposure in HCFs, consistent with a shift away from the myofibroblast phenotype. These observations provide descriptive, hypothesis-generating insight into potential regulatory patterns associated with atorvastatin treatment, although further functional studies are required to establish causal relationships and translational relevance. Full article

Oxidative stress contributes to vascular dysfunction and senescence-associated changes through activation of inflammatory and stress-responsive signaling pathways. Although the mammalian target of rapamycin (mTOR) integrates metabolic and redox-related signals, its role in vascular stress responses remains incompletely understood. In this study, we investigated the effects of Rapalink-1, an mTOR inhibitor, on H₂O₂-induced injury responses in human vascular endothelial cells (HUVECs) and vascular smooth muscle cells (SMCs). Oxidative stress-associated changes were assessed using oxidation-sensitive fluorescence, DNA damage markers (γ-H2AX and 8-OHDG), and senescence-associated readouts (SA-β-gal, Lamin B1, and p21). Senescence-associated secretory phenotype (SASP)-related factors were analyzed by qPCR and Western blot, and mTOR-, NF-κB-, and MAPK-related signaling was evaluated by Western blotting. H₂O₂ exposure reduced cell viability and increased oxidative stress-associated readouts, DNA damage markers, senescence-associated changes, and SASP-related factor expression in both HUVECs and SMCs. Rapalink-1 attenuated many of these responses, including oxidation-sensitive fluorescence, γ-H2AX and 8-OHDG staining, SA-β-gal positivity, Lamin B1 loss, p21 upregulation, and the expression of inflammatory and matrix-remodeling factors. These effects were accompanied by reduced phosphorylation of p65, p38, ERK1/2, S6, and 4EBP1. Overall, Rapalink-1 is associated with attenuation of oxidative stress-induced injury responses in vascular endothelial and smooth muscle cells, together with reduced NF-κB-, MAPK-, and mTOR-related signaling. These findings support further investigation of mTOR-targeted approaches in vascular aging and oxidative stress-related vascular dysfunction. Full article

We developed a multi-channel and multilayered polydimethylsiloxane (PDMS) microfluidic platform that integrates cyclic mechanical stimulation, independent reagent delivery, and real-time optical observation within a single device. The platform employs a four-layer architecture comprising a pneumatic valve control layer, an observation channel for cell culture and imaging (24 mm × 4 mm), a medium perfusion layer with independent inlet ports, and a vacuum actuation layer that deforms a 200 μm PDMS membrane under −20 kPa cyclic pressure at 1 Hz. Cyclic membrane strain of 10% was calibrated using fluorescent bead tracking and image analysis. Finite element analysis based on nonlinear Föppl–von Kármán plate theory confirmed that the central cell culture region (60% of membrane area) exhibits a mean von Mises strain of 14.2% with a uniformity of 81.3% (CV = 18.7%), validating relatively uniform mechanical stimulation across the culture surface. As a proof-of-concept, human aortic smooth muscle cells (CRL-1999) cultured under cyclic strain showed significant upregulation of HIF-1$\alpha$ expression (2.5-fold, $p<0.01$) and pronounced F-actin stress fiber alignment visualized by fluorescence microscopy, confirming the platform’s capability for mechanotransduction studies and real-time cellular observation. The multi-channel architecture enables multi-condition parallel testing by simultaneously introducing different reagent concentrations through independent inlet ports while maintaining identical mechanical parameters across all channels, providing a versatile tool for systematic investigation of cellular responses under controlled biomechanical conditions. Full article

Hydrolyzed collagen (HC) derived from salmon skin is a promising source of bioactive peptides. In this study, the vasorelaxant effects and potential mechanisms of action of HC on isolated rat thoracic aorta rings were investigated using the organ bath technique. The vasorelaxant properties of HC were evaluated using aortic rings from Wistar rats pre-contracted with phenylephrine (PE) or potassium chloride (KCl). HC induced significant vasorelaxation in both endothelium-intact and endothelium-denuded rings, indicating that its mechanism of action was independent of the endothelium and involved direct effects on vascular smooth muscle cells. The vasorelaxant effect of HC was reduced when pre-contraction was induced by tetraethylammonium chloride (TEA). However, the vasodilatory effects of HC were not significantly inhibited by all K⁺ channel blockers, including glibenclamide, barium chloride (BaCl₂), or 4-aminopyridine (4-AP). Additionally, pre-incubation with prazosin, an α-adrenoceptor blocker, significantly reduced the vasorelaxation induced by HC, whereas propranolol, a β-adrenoceptor blocker, had no effect. In addition, HC inhibited CaCl₂-induced contractions induced by both PE and caffeine in a Ca²⁺-free solution. Therefore, HC exhibited the vasorelaxant effects through an endothelium-independent mechanism. The vasodilatory effects of HC were associated with the activation of K_Ca channels, suppression of PE-induced contraction via α₁-adrenergic receptor pathways, and inhibition of CaCl₂-induced contractions by modulating intracellular Ca²⁺ release and extracellular Ca²⁺ influx in vascular cells. Full article

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease lacking therapies that target underlying cell death pathways. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, has emerged as a key mechanism in vascular remodeling. We investigated whether exogenous ketosis induced by ketone ester (KE) supplementation can suppress ferroptosis and prevent TAAD. TAAD was induced in C57BL/6 mice using β-aminopropionitrile (BAPN). A subset of these mice received KE [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate, 20 g/L] in their drinking water starting on day 15 of the BAPN treatment. Human aortic smooth muscle cells (HASMCs) were treated with the GPX4 inhibitor Ras-Selective Lethal 3 (RSL3) and β-hydroxybutyrate (β-OHB) to investigate ferroptotic markers, lipid peroxidation, and labile iron levels. KE supplementation significantly reduced TAAD incidence (69% → 43%) and improved survival rate (52% → 73%), while preserving aortic structure and reducing elastic fiber fragmentation. Transcriptomic analyses of human TAAD datasets (GSE153434 and GSE52093) and single-cell RNA sequencing data (GSE155468) revealed ferroptosis signatures characterized by decreased GPX4 and increased expression of iron metabolism genes. Mechanistically, KE suppressed BAPN-induced iron accumulation and lipid peroxidation in vivo. In HASMCs, β-OHB inhibited ferroptosis induced by GPX4 inhibition, decreasing lipid peroxidation and labile iron levels. KE restored GPX4 and SLC7A11 expression while suppressing HO-1 in vivo, with effects dependent on Nrf2 signaling in vitro. In summary, ketone ester supplementation protects against TAAD by inhibiting VSMC ferroptosis via GPX4 induction and HO-1 suppression, highlighting a potential therapeutic strategy for aortic disease. Full article