Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Background: Medial arterial calcification is a common lesion associated with aging, chronic kidney disease, and diabetes that can lead to poor outcomes. Because the calcification is extensive when first apparent clinically or even radiologically, optimal therapy should target reversal in addition to prevention. However, studies to date suggest that medial calcification is irreversible under physiological conditions. This lack of reversal was investigated further by implanting calcified human arteries or hydroxyapatite subcutaneously into mice, or culturing them with murine osteoclasts in vitro.

Methods: Calcified human tibial arteries, obtained from amputations and previously frozen, were implanted subcutaneously in the dorsum of mice. Mineral content was measured by microcomputed tomography before and after implantation and compared with the calcium content of implanted pure hydroxyapatite or murine bone particles, along with histology. Calcified arteries were also incubated in vitro with osteoclasts generated by treating murine macrophages with receptor activator of NF-κB (nuclear factor kappa B).

Results: There was no decrease in mineral content of implanted arteries over 6 weeks and only minimal loss of calcium in devitalized bone particles, compared with almost complete resorption of hydroxyapatite. No resorption of hydroxyapatite occurred when implanted within a cell-impermeable diffusion chamber. Multinucleated giant cells, negative for osteoclast markers, were numerous among implanted hydroxyapatite, but rare in implanted arteries and bone. There was no histological evidence of resorption in calcified arteries incubated with osteoclasts.

Conclusions: Hydroxyapatite is readily reabsorbed in vivo by a cell-mediated process not involving osteoclasts. The lack of resorption of medial arterial calcifications, even in the presence of osteoclasts, indicates that calcifications have properties that prevent cell-mediated resorption. Further studies are needed to identify these properties and develop strategies to overcome this.

Advances in cancer therapies have transformed many malignancies into chronic or manageable conditions, but these treatments have been linked to adverse 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.

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.

The delivery of insulin to the skeletal muscle has a major influence on glucose disposal in muscle, where 80% of total body glucose disposal occurs. The skeletal muscle microvascular endothelial cells play a critical role in peripheral insulin sensitivity through their regulation of insulin delivery. Recent advancements in methodologies have provided in-depth views of the molecular mechanisms by which the endothelial cells regulate the delivery process. However, how the cellular machinery is modulated under physiological or pathological conditions remains largely unexplored. Conditions with estrogen deficiency and obesity are 2 situations that are closely associated with peripheral insulin resistance and type 2 diabetes in humans. It is of great interest to determine whether and how endothelial control of insulin delivery impacts the development of metabolic dysregulation under these and other conditions. This review aims to provide an overview of the molecular mechanisms governing insulin delivery to the skeletal muscle. The available evidence will be presented that the transcytosis of insulin across the endothelial cell monolayer in skeletal muscle plays a critical role in muscle insulin delivery, thereby having a major impact on overall glucose homeostasis. In vivo investigations with manipulation of mechanisms in endothelial cells will be summarized, and the current knowledge gaps will be presented. Interrogation of the role of the endothelium in insulin transport provides a paradigm in which insights are being gained about cellular actions of insulin, molecular transport by endothelial cells, and the intricacies of glucose homeostasis.

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.

Results: We established that unidirectional laminar shear stress regulates CXCR4 via endocardial NOTCH signaling through upregulation of CXCR4 ligand SDF1. 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.

Pericytes are mural cells that line capillaries throughout the brain, retina, lung, and other organs, where they support capillary homeostasis through direct contact and paracrine crosstalk with capillary endothelium. Despite being described more than a century ago, their contributions to health and vascular diseases remain unclear, largely due to the difficulty of definitive identification. Their inherent plasticity, as well as shared markers and close lineage relationships with other mural cells, results in overlap in identification and underrepresentation in single-cell data sets. Emerging evidence reveals that pericytes play a critical role in the vascular remodeling characteristics of pulmonary hypertension, via mechanisms involving smooth muscle-like phenotypic switching and morphological changes influenced by hypoxia signaling, transforming growth factor-β, cyclic GMP modulation, and disrupted pericyte-endothelial communication (eg, Wnt5a). Recent single-cell RNA sequencing enabled the identification of a novel and specific pericyte marker, Higd1b, thereby improving pericyte identification and revealing novel pericyte subtypes. In this review, we summarize historical and recent insights into pericyte morphology and function, their increasingly recognized role in pulmonary hypertension pathobiology, and the potential to unlock novel therapeutic avenues targeting pericytes.

Background: Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary heart disease (CHD) has been called into question. Protein-based minor HDL subspecies are emerging as novel and likely causal biomarkers, direct or inverse, for risk of CHD, diabetes, and other conditions. HDL-raising drugs such as CETP (cholesteryl ester transfer protein) inhibitors raise certain HDL subspecies that have adverse effects on CHD risk. We hypothesize that dietary unsaturated fat, protein, and carbohydrate differentially affect 15 minor protein-based HDL subspecies with diverse functionality in lipid metabolism, antioxidation, immunity, hemostasis, and protease inhibition.

Methods: We analyzed the apo (apolipoprotein) A1 concentrations of 15 minor HDL subspecies after 4 weeks on each diet in 141 participants in the OmniHeart trial (Optimal Macronutrient Intake Trial to Prevent Heart Disease), a randomized 3-period crossover, controlled feeding study. The diet rich in carbohydrate contained 58% carbohydrate, 27% fat, and 15% protein, and the diets rich in unsaturated fat and protein replaced 10% of carbohydrate with unsaturated fat and protein, respectively.

Results: Unsaturated fat replacing dietary carbohydrate increased concentrations of apoA1 in lipid metabolism subspecies including HDL that contains apoA2, apoE, or apoC1 that has been associated with reduced risk of CHD. Protein replacing carbohydrate increased apoE HDL, consistent with lower CHD risk, and decreased concentrations of several other HDL subspecies that were associated with higher risk of CHD including HDL that contains PLMG (plasminogen), A2M (alpha-2-macroglobulin), or apoL1. Network analysis showed connections between functional groups of HDL subspecies that are quantitatively affected by dietary macronutrients.

Conclusions: Replacing dietary carbohydrate with unsaturated fat or protein raised levels of protein-based HDL subspecies associated with lower risk of CHD or lowered the levels of those associated with higher risk of CHD. Minor HDL subspecies with diverse functions may mediate the association of dietary patterns with risk of CHD.

Background: Perivascular adipose tissue (PVAT) fine-tunes blood vessel contractility and vascular homeostasis. During obesity and atherosclerosis, PVAT becomes dysfunctional and loses its anticontractile potential. Previously, we reported that global knockout of adipose triglyceride lipase (ATGL), the major enzyme responsible for the breakdown of triglycerides, has the potential to modify PVAT functions. To address the causal relationship between PVAT lipolysis and blood vessel contractility, we analyzed ex vivo vasomotor function of mice with tissue-specific rescue/overexpression or knockout of ATGL in adipose tissue.

Methods: To generate mice lacking ATGL in all tissues except for adipose tissue (ATGL knockout with adipocyte-specific expression of ATGL [A+/AKO]), we crossed adipocyte ATGL-rescued (A+) mice with ATGL-deficient (ATGL knockout [AKO]) mice. Body weight, plasma levels of fatty acids, and blood glucose were compared between A+/AKO and AKO mice. Ex vivo vasoreactivity studies were performed in the absence and presence of PVAT to test for acute and chronic effects of PVAT on vascular function.

Results: Adipocyte-rescued AKO mice (A+/AKO) had significantly less amounts of PVAT than AKO controls while displaying moderate ATGL expression. A+/AKO aortas exhibited decreased anticontractile effects of PVAT compared with AKO aortas. This effect on contractile function was observed in an agonist-specific manner without affecting smooth muscle cell function or endothelium-dependent relaxation. Assessment of cardiac function using the Langendorff setup revealed that adipocyte ATGL selectively modulated vascular contractility without affecting systolic or diastolic performance. Studies using mice that express ATGL solely in cardiac muscle and adipocyte-specific ATGL knockout mice verified our findings in A+/AKO mice, revealing acute and chronic effects of adipocyte lipolysis on vasoreactivity.

Conclusions: We provide the first evidence that changes in adipocyte lipolysis have the potential to regulate blood vessel contractility. Ablation of ATGL in adipocytes decreases vascular contractility and, thus, has the potential to prevent PVAT dysfunction in obesity and atherosclerosis.

Background: Abdominal aortic aneurysm (AAA), a pathological dilation of the abdominal aorta, is primarily driven by chronic aortic wall inflammation. The well-established anti-inflammatory microRNA 146a (miR-146a) has been implicated as a key regulator in various chronic inflammatory pathologies. However, its potential functional role in the pathogenesis of AAA remains to be elucidated.

Methods: We constructed Ang II (angiotensin II)-induced and PPE (porcine pancreatic elastase)-induced models in global miR-146a knockout mice, vascular smooth muscle cell (VSMC)-specific miR-146a knockout mice, and macrophage-specific miR-146a knockout mice, respectively, to explore the role of miR-146a in AAA. Western blot, quantitative polymerase chain reaction, and immunohistochemistry were used to detect the levels of aortic proinflammatory markers and VSMC contractile proteins, whereas flow cytometry was used to assess M1/M2-like macrophage polarization. To validate the downstream mechanism, dibenzazepine was intraperitoneally injected to inhibit the Notch1 pathway in rescue experiments.

Results: In the Ang II-induced and PPE-induced model, global knockout of miR-146a promoted AAA development, increased maximal aortic diameter, exacerbated medial elastin degradation, and upregulated aortic proinflammatory markers (COX2 [cyclooxygenase 2], MMP [matrix metalloproteinase] 2, MMP9, and CCL2 [chemokine (C-C motif) ligand 2]). Flow cytometry analysis revealed that global miR-146a deficiency also induced macrophage polarization toward the inflammatory M1 phenotype. Conditional deletion of miR-146a in VSMCs and macrophages largely replicated AAA formation and proinflammatory effects. Furthermore, AAV9 (adeno-associated virus)-mediated miR-146a knockdown significantly reduced VSMC contractile proteins CNN1 (calponin 1), SM22α (smooth muscle 22α), and α-SMA (α-smooth muscle actin) in mouse aortas at 7 days post-Ang II perfusion. Mechanistically, Notch1 antagonist dibenzazepine effectively rescued AAA characteristics and M1 biomarkers while enhancing M2 biomarkers in global miR-146a knockout mice.

Conclusions: The absence of miR-146a potentiates AAA formation by promoting VSMC phenotypic switching, Notch1 signaling-mediated aortic inflammation, and macrophage M1 polarization. Thus, miR-146a plays a critical role in maintaining aortic structural integrity to prevent aneurysmal pathogenesis.