Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Viral hemorrhagic fever (VHF) describes different diseases caused by several viruses from 6 virus families: Filoviridae, Nairoviridae, Phenuiviridae, Hepadnaviridae, Arenaviridae, and Flaviviridae. VHF was once considered a geographically localized problem, but due to expanding vector ranges and increased human contact with animal reservoirs and hosts, the number of VHF cases is increasing. As the name indicates, VHF is associated with bleeding. Both direct effects from viral infection of host cells and indirect effects caused by the host response to the virus contribute to dysregulation of the hemostatic system. Many studies have measured different parameters and various biomarkers in samples from infected humans and nonhuman primate models. For example, Ebola virus infection in a nonhuman primate model leads to increased TF (tissue factor) expression in peripheral blood mononuclear cells and extracellular vesicles. In dengue virus infection, thrombocytopenia and platelet dysfunction occur. There are likely both common and distinct mechanisms underlying bleeding in different VHFs, as sites of bleeding differ between the viruses. Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability. While a significant body of work exists examining different aspects of the various viral infections that may lead to bleeding, there are still many open questions and areas for investigation. Therefore, more studies are needed to better understand the mechanisms underlying bleeding in VHF caused by different viruses.

Advances in cancer therapies have transformed many malignancies into chronic or manageable conditions, but have been linked to adverse, including cardiovascular, events. Vascular toxicities associated with cancer treatment range from abnormal vasoreactivity to accelerated atherosclerosis, arterial thrombotic events, vasculitis, and arterial aneurysms or dissections. 5-fluorouracil and VEGF (vascular endothelial growth factor) inhibitors are the agents most commonly linked to abnormal vasoreactivity, whereas BCR-ABL (breakpoint cluster region-Abelson murine leukemia viral oncogene homolog) inhibitors and immune checkpoint inhibitors have been associated with accelerated atherosclerosis. Arterial thrombotic events are seen with VEGF and BCR-ABL inhibitors as well as platinum drugs. Vasculitis emerged with the use of immune checkpoint inhibitors, and arterial aneurysms and dissections with VEGF inhibitors. Radiation therapy can lead to several of the outlined vascular toxicities. This review comprehensively explores the mechanisms of vascular complications associated with chemotherapy, targeted therapies, immunotherapies, and radiation therapy. Key contributors include endothelial injury and dysfunction, oxidative stress, and inflammation. An understanding of the mechanisms of vascular toxicities may facilitate optimal treatment and preventive strategies in patients with cancer.

C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally developed for the treatment of hereditary angioedema associated with C1INH deficiency. A growing body of literature indicates that C1INH products may find utility in the management of several other disease states. In this review, we detail the key biological activities of C1INH and consider the pathophysiological role of C1INH targets in many conditions. The therapeutic potential of exogenous C1INH is highlighted in the settings of thromboembolism, ischemia-reperfusion injury, sepsis, transplantation, and coronavirus disease 2019.

Zebrafish possess a remarkable capacity to regenerate cardiac tissues after injury, offering a powerful model to dissect the cellular and molecular mechanisms driving heart regeneration. Immune cells play distinct and context-dependent roles during regeneration, from debris clearance and inflammation resolution to modulation of cell proliferation and fibrosis. Here, we review the distinct contributions of neutrophils, macrophages, and lymphoid cells during zebrafish heart regeneration, with a focus on their temporal coordination and regulatory signaling pathways. Understanding proregenerative immune-mediated mechanisms may identify therapeutic targets to enhance cardiac repair in disease contexts, such as myocardial infarction and heart failure.

Background: Distinct plaque morphologies underlie the major causes of acute coronary syndrome and sudden cardiac death. We used polygenic risk scores (PRSs) for hypercholesterolemia and hypertriglyceridemia, 2 major risk factors for coronary artery disease (CAD), to evaluate the relative contributions of these risk factors to specific plaque morphologies, specifically plaque rupture and erosion.

Methods: DNA was extracted from formalin-fixed paraffin-embedded tissues and genotyped for 954 subjects from our sudden death autopsy registry, with cause of death determined by autopsy. LDL (low-density lipoprotein)-specific and triglyceride-specific PRSs were constructed based on the Global Lipids Genetics Consortium genome-wide association study results, excluding variants associated with both traits (P<0.05).

Results: Subjects in the highest LDL-specific PRS quintile had significantly more plaque rupture, ≥75% lumen narrowing, thrombotic CAD, and CAD-related death compared with those in the lowest quintile. After adjusting for the first 10 principle components, LDL-specific PRS remained significantly associated with rupture (odds ratio [OR], 1.22 per SD [95% CI, 1.04-1.43]; P=0.017), ≥75% lumen narrowing (OR, 1.33 [95% CI, 1.13-1.57]; P<0.001), thrombotic CAD (OR, 1.21 [95% CI, 1.04-1.41]; P=0.016), and CAD-related death (OR, 1.31 [95% CI, 1.13-1.52]; P<0.001). In contrast, triglyceride-specific PRS was significantly associated with thrombotic CAD (OR, 1.20 [95% CI, 1.03-1.40]; P=0.020) and showed a trend toward association with plaque rupture (OR, 1.15 [95% CI, 0.98-1.35]; P=0.091). No association was observed between LDL-/triglyceride-specific PRS and plaque erosion.

Conclusions: This is the first study to associate lipid PRSs with specific plaque morphologies, revealing distinct pathogenic mechanisms underlying plaque rupture and erosion. Early genetic risk stratification and subsequent lipid-lowering interventions may provide substantial clinical benefits in mitigating cardiovascular risk, particularly in relation to plaque rupture. Our findings raise questions about the effectiveness of such strategies in preventing plaque erosion, suggesting the need for further investigation into its underlying pathogenesis.

Background: Much is known about the genetic regulation of early valvular morphogenesis, but mechanisms governing later fetal valvular remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Apparent side-specific expression of valvulogenic programs motivates the hypothesis that shear stress pattern-specific endocardial signaling directs the remodeling and maturation of valve leaflets. Here, we aim to determine how local hemodynamic stress regulates the maturation of fetal semilunar heart valves.

Methods: We identified strong ventricularis-specific expression of endocardial NOTCH1 and mesenchymal CXCR4 (C-X-C chemokine receptor type 4) during fetal valve stages. Valve cell-type specific conditional Notch and Cxcr4 mouse deletions were generated and analyzed in vivo consequences, which were then tested directly using ex vivo chick endocardial cells and valve organoids via gain and loss of function approaches. Samples were then quantitatively analyzed via histology, immunohistochemistry, and qRT-PCR (quantitative real-time polymerase chain reaction).

Results: We established that unidirectional laminar shear stress regulates CXCR4 via endocardial NOTCH signaling through upregulation of CXCR4 ligand SDF1 (stromal cell-derived factor 1). Global deletion and endocardium-derived mesenchymal cell-specific deletion of Cxcr4 both resulted in hyperproliferative and thickened outflow tract valves. In addition, conditional ablation of Cxcr4 also revealed that it promotes matrix remodeling and tissue compaction through inhibition of BMP (bone morphogenetic protein) and WNT signaling programs.

Conclusions: High-magnitude unidirectional laminar shear stress is transduced by endocardial cells, turning on a NOTCH1/CXCR4 molecular switch. This switch stops the valve mesenchymal growth program by inhibiting WNT/BMP. Simultaneously, it also orchestrates valve condensation, mesenchymal cell differentiation, and ECM (extracellular matrix) remodeling. Taken together, our findings identify a novel molecular switch controlled by local hemodynamic cues that directs valve maturation robustly in a side-specific manner.

Background: Recent evidence points to connections between HDLs (high-density lipoproteins), the coagulation system, and venous thromboembolism occurrence. However, uncertainty remains regarding the impact of specific HDL characteristics on the coagulation system. This study investigated associations between HDL characteristics and hemostatic parameters in a large middle-aged Dutch population.

Methods: Using baseline measurements from 6245 participants in NEO study (the Netherlands Epidemiology of Obesity), we performed adjusted linear regression analyses to estimate associations between 34 parameters of XLHDL (very large HDL), LHDL (large HDL), MHDL (medium HDL), and SHDL (small HDL) particles, as well as ApoA1 (apolipoprotein A1), quantified using a high-throughput ¹H-nuclear magnetic resonance metabolomics platform, and coagulation parameters. These included coagulation factor (F) VIII, FIX, FXI, and fibrinogen, along with 5 parameters of the thrombin generation potential. In addition, the associations between HDL characteristics and parameters of platelet activation and endothelial glycocalyx health were tested in a subpopulation.

Results: Our findings revealed a particle size-dependent association between HDL parameters and coagulation parameters. Particularly, per 1-SD increase in the levels of components within XLHDL (very large HDL), we observed lower levels in FIX and FXI activities, endogenous thrombin potential, and peak height (median β [interquartile range], FIX: 3.26% [-3.50% to -3.18%]; FXI: -0.96% [-1.21% to -0.89%]; endogenous thrombin potential: -22.11 [-27.07 to -21.47] nmol/L·min; and peak height: -2.28 [-2.70 to -2.19] nmol/L), indicating an antithrombotic effect. In contrast, per 1-SD increase in the levels of components within MHDL and SHDL, we observed an increase in endogenous thrombin potential, peak height, and activities of FVIII, FIX, and FXI, indicating a prothrombotic effect. HDL characteristics were not associated with platelet activation parameters or with glycocalyx-related parameters.

Conclusions: Our study provides evidence for a size-dependent relationship between HDL components and coagulation parameters. These findings contribute to a better understanding of the potential role of HDL in the pathogenesis of venous thromboembolism.

Background: Deep vein thrombosis (DVT) is a prevalent peripheral vascular disorder associated with abnormal epigenetic processes and altered gene expression in endothelial cells. Accumulating evidence has demonstrated that NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine modification exerts unique roles in ferroptosis, but its roles are still elusive in DVT.

Methods: To explore the potential mechanism of NAT10 and ferroptosis on thrombogenesis, we used NAT10 and GPX4 (glutathione peroxidase 4) knockout mice as an in vivo model, and utilized techniques, such as RNA immunoprecipitation, acRIP-qPCR (acetylated RNA immunoprecipitation-quantitative PCR), N4-acetylcytidine Dot Blotting assay, and Western blotting, for detailed molecular analysis.

Results: GPX4 is a pivotal gene that suppresses ferroptosis. Utilizing endothelial cell-specific GPX4 conditional knockout mice (GPX4^fl/flCdh5-Cre⁺), we proved that ferroptosis in endothelial cells promotes the formation of thrombosis. Previous evidence indicates that NAT10 overexpression induces ferroptosis and downregulates GPX4 expression. Here, we found that NAT10 expression was elevated in DVT mice, and silencing of NAT10 markedly attenuated ferroptosis both in vitro and in vivo. Furthermore, endothelial cell-specific knockout of NAT10 (NAT10^fl/flCdh5-Cre⁺) demonstrated a reduction in endothelial ferroptosis, thereby inhibiting both the formation and progression of DVT. Mechanistic studies indicated that NAT10 facilitated the N4-acetylcytidine modification of HMOX1 (heme oxygenase 1), which enhanced its mRNA stability, leading to the accumulation of ferrous ions, and exacerbating endothelial dysfunction in DVT.

Conclusions: Collectively, our data elucidate that downregulation of NAT10 mitigates endothelial ferroptosis and prevents DVT formation and progression by modulating HMOX1 expression, which offers a potential novel strategy for the prevention and treatment of thrombosis in DVT.

Background: Eradicating endothelial caveolae by deleting the Cav1 (caveolin-1) gene reduces LDL (low-density lipoprotein) uptake in arteries and efficiently prevents early atherogenesis, but the role in established atherosclerosis is unknown. Here, to examine CAV1 as a potential therapeutic target, we deleted endothelial Cav1 in mice after lesion development and analyzed the effect on LDL uptake and lesion progression.

Methods: To allow timed endothelium-specific Cav1 deletion, we generated male and female mice with floxed Cav1 alleles and endothelium-specific inducible Cre recombinase. Atherosclerosis was induced by virus-mediated PCSK9 (proprotein convertase subtilisin/kexin type 9) gene transfer and a high-cholesterol diet. After 16 weeks of lesion development, endothelial Cav1 deletion was induced by a series of tamoxifen injections, repeated after 4 weeks, and the mice were followed for another 4 weeks. Mice were injected with fluorescently labeled LDL at 1 and 18 hours before euthanasia to study uptake and retention in lesions. Sections of the aortic root were analyzed for lesion size, composition, and LDL accumulation.

Results: Efficient conditional knockout of endothelial Cav1 was confirmed by CAV1 immunostaining and by the loss of caveolae by electron microscopy. Loss of endothelial Cav1 for 8 weeks reduced LDL entry into lesions but did not significantly decrease LDL retention, lesion lipid accumulation, fibrous tissue, or lesion size. In males, a reduction in macrophages was seen.

Conclusions: Targeting CAV1 does not efficiently block LDL entry or reduce lesion progression in established atherosclerosis. These findings open several questions for further research, including alternative LDL entry mechanisms that could circumvent caveolar transport in established atherosclerosis.

Background: The application or excessive exposure to glucocorticoids constitutes a common adverse factor endured by intrauterine fetuses. Gestational glucocorticoids' exposure is intimately associated with the risk of postnatal vascular problems; however, whether the vascular problem can be transgenerationally inherited remains indistinct. In this study, a mouse model of gestational glucocorticoids' exposure was established, aiming to discover the abnormal phenotype of acquired vascular function of the offspring and clarify the epigenetic mechanism of the transgenerational transmission of the relevant abnormal phenotypes.

Methods: To model gestational glucocorticoid exposure, pregnant mice received intraperitoneal injections of dexamethasone (a synthetic glucocorticoid) on gestational days 12, 14, 16, and 18. Male offspring (F1) derived from dexamethasone group-exposed pregnancies were bred with wild-type females to generate F2 progeny, and this breeding strategy was repeated to produce F3 offspring. Adult male offspring from all 3 generations were subsequently analyzed.

Results: We observed that gestational dexamethasone group exposure induced a modest but consistent elevation in systolic blood pressure across F1 to F3 male offspring, accompanied by enhanced Ang II (angiotensin II)-mediated vascular contractility. Mechanistically, dexamethasone group exposure significantly reduced DNA methylation in the Agtr1a (Ang II receptor subtype A) gene promoter within F1 offspring vasculature, leading to upregulated Agtr1a expression and heightened oxidative stress via the AT1R (Ang II receptor 1)/NOX (nicotinamide adenine dinucleotide phosphate oxidase) 2/reactive oxygen species axis. This cascade potentiated Ang II-induced vascular contractility. Moreover, these acquired abnormal vascular problems can be stably inherited and transgenerationally transmitted through the alteration of the DNA methylation pattern of the Agtr1a gene in sperm.

Conclusions: This study demonstrates that gestational glucocorticoids' exposure triggers transgenerational inheritance of vascular dysfunction in male offspring via DNA methylation reprogramming, providing direct evidence for the epigenetic transmission of acquired traits. These findings advance our understanding of intergenerational disease mechanisms and offer novel insights for clinical strategies aimed at mitigating the adverse effects of gestational glucocorticoid therapy.