Semaglutide treatment attenuates vessel remodelling in ApoE-/- mice following vascular injury and blood flow perturbation.

Background And Aims: Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque.

Methods: In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks.

Role of mechanical stress and neutrophils in the pathogenesis of plaque erosion.

Mechanical stress is a well-recognized driver of plaque rupture. Likewise, investigating the role of mechanical forces in plaque erosion has recently begun to provide some important insights, yet the knowledge is by far less advanced. The most significant example is that of shear stress, which has early been proposed as a possible driver for focal endothelial death and denudation.

Synthesis of cationic quaternized pullulan derivatives for miRNA delivery.

Pullulan is a natural polysaccharide of potential interest for biomedical applications due to its non-toxic, non-immunogenic and biodegradable properties. The aim of this work was to synthesize cationic pullulan derivatives able to form complexes with microRNAs (miRNAs) driven by electrostatic interaction (polyplexes). Quaternized ammonium groups were linked to pullulan backbone by adding the reactive glycidyltrimethylammonium chloride (GTMAC).

Relationship of Iron Deposition to Calcium Deposition in Human Aortic Valve Leaflets.

Background: Intraleaflet hematomas are associated with advanced stages of aortic valve calcification and suspected to be involved in disease progression. However, the mechanism by which the entry of blood cells into the valves affects the biology of aortic valvular interstitial cells (VICs) remains to be elucidated.

Objectives: This study sought to evaluate the putative link between intraleaflet hematoma and aortic valve calcification and to assess its pathophysiological implications.

Haemodynamic stress-induced breaches of the arterial intima trigger inflammation and drive atherogenesis.

Aims: Inflammatory mediators, including blood cells and their products, contribute critically to atherogenesis, but the igniting triggers of inflammation remain elusive. Atherosclerosis develops at sites of flow perturbation, where the enhanced haemodynamic stress could initiate the atherogenic inflammatory process due to the occurrence of mechanic injury. We investigated the role of haemodynamic stress-induced breaches, allowing the entry of blood cells in the arterial intima, in triggering inflammation-driven atherogenesis.

Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production Through Interleukin-1α and Cathepsin G.

Objective- Coronary artery thrombosis can occur in the absence of plaque rupture because of superficial erosion. Erosion-prone atheromata associate with more neutrophil extracellular traps (NETs) than lesions with stable or rupture-prone characteristics. The effects of NETs on endothelial cell (EC) inflammatory and thrombogenic properties remain unknown.

Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion.

Rationale: Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme's role in atherothrombosis remains scant.

Mechanisms of erosion of atherosclerotic plaques.

Purpose Of Review: The present review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis.

Recent Findings: Human coronary artery atheroma that give rise to thrombosis because of erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs).

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

Rationale: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation.

Objective: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion.

Diameter and thickness-related variations in mechanical properties of degraded arterial wall in the rat xenograft model.

The purpose of this study was to evaluate the diameter and thickness-related variations in mechanical properties of degraded arterial wall. To this end, ring tests were performed on 31 samples from the rat xenograft model of abdominal aortic aneurysm (AAA) and failure properties were determined. An inverse finite element method was then employed to identify the material parameters of a hyperelastic and incompressible strain energy function.

MicroRNA-181b inhibits thrombin-mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10.

Thrombogenic and inflammatory mediators, such as thrombin, induce NF-κB-mediated endothelial cell (EC) activation and dysfunction, which contribute to pathogenesis of arterial thrombosis. The role of anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Our previous study demonstrated that miR-181b inhibits downstream NF-κB signaling in response to TNF-α.

Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques.

Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown.

Evidence of estrone-sulfate uptake modification in young and middle-aged rat prostate.

High plasma exposure to estrogens is often associated with prostate cancer. Reducing this phenomenon may present therapeutic benefits. The involvement of estrone sulphate (E1S), the most abundant circulating estrogen in men, has been partially studied in this age-related pathology.

TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion.

Aims: Superficial erosion of atheromata causes many acute coronary syndromes, but arises from unknown mechanisms. This study tested the hypothesis that Toll-like receptor-2 (TLR2) activation contributes to endothelial apoptosis and denudation and thus contributes to the pathogenesis of superficial erosion.

Methods And Results: Toll-like receptor-2 and neutrophils localized at sites of superficially eroded human plaques.

Chemokine (C-X-C motif) receptor 4 blockade by AMD3100 inhibits experimental abdominal aortic aneurysm expansion through anti-inflammatory effects.

Objective: Inflammation plays a critical role in the development of abdominal aortic aneurysms (AAAs). Because stromal cell-derived factor 1 (SDF-1) is known for its ability to attract inflammatory cells, we investigated whether SDF-1/chemokine (C-X-C motif) receptor 4 (CXCR4) axis is expressed in aneurysmal aortic wall and plays a role in AAA physiopathology and asked whether its blockade modulates AAA formation and expansion.

Approach And Results: Quantitative real-time polymerase chain reaction analysis showed that SDF-1α and CXCR4 mRNA levels are increased in both human and CaCl2-induced mouse AAA wall and are positively correlated to the aortic diameter in mice.

Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata.

Objective: Substantial evidence implicates interstitial collagenases of the matrix metalloproteinase (MMP) family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions, therefore, has important clinical implications. This study assessed in mice the relative effect of the 2 principal mouse collagenases on collagen content and other plaque characteristics.

Reestablishment of the endothelial lining by endothelial cell therapy stabilizes experimental abdominal aortic aneurysms.

Background: Loss of the endothelium and its replacement by a thick thrombus are structural features of human abdominal aortic aneurysms (AAAs). In AAAs, the relationship between aortic diameter expansion, the presence of thrombus, and the lack of endothelial cells (ECs) remains unexplored. We hypothesized that reendothelialization by cell therapy would modulate aortic wall destruction and ultimately stabilize AAAs.

Long term stabilization of expanding aortic aneurysms by a short course of cyclosporine A through transforming growth factor-beta induction.

Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion.