Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Preeclampsia, a condition characterized by new-onset hypertension during pregnancy and ≥1 indices of organ damage, is a major driver of both short- and long-term maternal health outcomes. Individuals with a history of preeclampsia are at increased risk for cardiovascular, renal, and other chronic diseases. Recent studies have linked preeclampsia history with increased risk of dementia later in life, underscoring the importance of new guidelines emphasizing blood pressure control to reduce the risk of cognitive decline. Unfortunately, neither the mechanisms underlying the causes of preeclampsia nor their links with cognitive function are well understood. Vascular contributions to cognitive impairment and dementia are a type of dementia caused by reduced cerebral blood flow, often resulting from vascular dysfunction associated with small vessel damage or chronic hypertension. The renin-angiotensin-aldosterone system (RAAS) is a hormone system with a major role in regulating blood pressure, fluid homeostasis, and vascular function inside and outside of pregnancy. The RAAS is markedly activated during pregnancy; preeclampsia is associated with disruptions in the normal activity of the RAAS, including excessive Ang (angiotensin) II type 1 receptor signaling, and loss of protective effects of Ang-(1-7) and Ang II type 2 receptors. Preexisting hypertension may impair the normal RAAS response to pregnancy, increasing susceptibility to vascular damage both during and after pregnancy. Results from human and animal studies indicate that dysregulation of the RAAS is a shared pathway underlying vascular dysfunction in both preeclampsia and vascular contributions to cognitive impairment and dementia, suggesting a mechanistic link between these 2 conditions. Persistent endothelial damage, impaired vascular remodeling, and chronic activation of Ang II type 1 and mineralocorticoid receptor signaling may increase long-term risk. This connection underscores the importance of monitoring and managing blood pressure during pregnancy and in women with a history of preeclampsia to mitigate the risk of dementia.

Pediatric hypertriglyceridemia is common in youths, affecting 10% to 20% of US children and adolescents, and is increasingly recognized because of its association with obesity, insulin resistance, and steatotic liver disease. Hypertriglyceridemia can lead to life-threatening acute pancreatitis, and prolonged exposure may increase risk of atherosclerotic cardiovascular disease. Screening for pediatric dyslipidemia has been recommended by a number of society guidelines; however, screening rates remain suboptimal. Treatment includes a multidisciplinary approach focused on increasing physical activity, dietary interventions, and pharmacotherapy. This scientific statement outlines triglyceride metabolism and the pathophysiology of hypertriglyceridemia and provides an evidence-based review of the current literature on the screening, diagnosis and management of pediatric hypertriglyceridemia. This review highlights the need for additional research for effective lifestyle and pharmacotherapy for the treatment of pediatric hypertriglyceridemia.

Background: Chronic left-to-right shunting, as occurs with congenital heart disease or persistent ductus-like flow, exposes pulmonary circulation to sustained high-flow shear and pulsatile pressure and causes severe, flow-mediated arteriopathy. A scalable, minimally invasive mouse model that reproduces this hemodynamic trigger is needed to enable mechanistic dissection in a genetically tractable system.

Methods: An ultrasound-guided transcatheter aortopulmonary shunt) procedure was developed to create ductus-like communication between the aortic arch and pulmonary artery. Shunt formation and patency were confirmed by B-mode echocardiography with color and pulsed-wave Doppler. Hemodynamics and right ventricular function were assessed by transthoracic echocardiography and closed-chest micromanometer catheterization at 1 month after surgery. A subset of animals was analyzed at 14 days for early endothelial plasticity. Bulk RNA sequencing of pulmonary arteries was performed to define transcriptional remodeling associated with shunt-driven disease.

Results: Transcatheter aortopulmonary shunt produced a sustained left-to-right overcirculation with Doppler-confirmed shunt flow, which induced pulmonary artery hypertension with elevated right ventricular systolic pressure, increased pulmonary vascular load, and progressive right ventricular dilation and dysfunction. Histological analyses demonstrated robust pulmonary arterial remodeling, including medial muscularization and thickening, adventitial expansion, and perivascular fibrosis, accompanied by right ventricular cardiomyocyte hypertrophy and increased myocardial fibrosis. Transcriptomic profiling of pulmonary arteries revealed broad differential gene regulation consistent with pulmonary artery hypertension pathobiology, including inflammatory, proliferative, and profibrotic responses and increased mesenchymal/smooth muscle marker expression. Costaining endothelial and mesenchymal markers supported endothelial phenotypic transition within the remodeled pulmonary arterial wall.

Conclusions: Transcatheter aortopulmonary shunt establishes a minimally invasive, reproducible murine model of shunt-driven pulmonary artery hypertension triggered by flow-mediated arteriopathy. This platform provides a versatile tool to interrogate flow-sensing mechanisms and to evaluate therapies targeting both vasoreactivity and structural remodeling in pulmonary artery hypertension.

Background: Impaired angiogenesis underpins cardiovascular disease, particularly in people with diabetes; however, molecular mechanisms are still poorly understood. This study aims to decipher the role of an emerging antiangiogenic protein, FKBPL (FK506-binding protein-like), on cardiac structure and function, vascular integrity, and inflammatory signaling in in vivo and in vitro models of diabetes.

Methods: In vivo, FKBPL transgenic mice (fkbpl^+/-) were used to examine the metabolic and cardiovascular function and FKBPL-mediated mechanisms in streptozotocin-induced diabetes. In addition, comprehensive in vitro assessments of endothelial function and mechanisms were performed in normal/high-glucose and high/low-FKBPL conditions.

Results: Fkbpl^+/- mice show signs of early cardiac remodeling (increased E/A ratio, P=0.047, and cardiomyocytes size, P=0.0018; reduced collagen deposition, P=0.013; col1a1 mRNA reduction, P=0.0028) and aberrant expression of cardiac vascular dysfunction proteins (ICAM-1 [intercellular adhesion molecule 1], P<0.001, SIRT-1 [sirtuin 1]; P<0.001). Proinflammatory cardiac profile was prominent in fkbpl^+/- murine hearts with increased protein expression of ICAM-1, IL (interleukin)-12p40, IL-15, IL-22, LIF (leukemia inhibitory factor), lipocalin-2, MMP (matrix metalloproteinase)-3/-9, periostin, serpin E1, and VCAM-1 (vascular cell adhesion molecule 1), which were decreased in diabetes. In diabetic mice with low FKBPL expression, glucose metabolism deteriorated, whereas vascular dysfunction improved. In normal glucose conditions, FKBPL knockdown in human aortic endothelial cells reduced VE-cadherin (vascular endothelial cadherin; P=0.0016) and impaired endothelial barrier (P<0.001). In high-glucose conditions, endothelial FKBPL knockdown improved angiogenesis, however overexpression of FKBPL reduced angiogenesis by inhibiting the FGF (fibroblast growth factor) 2 and PDGF (platelet-derived growth factor) pathways (P<0.001) and increasing proinflammatory pathways (TGF [transforming growth factor]-β, P<0.001; leukocyte migration, P=0.033; IL-7 signaling, P=0.039), by upregulating miR-29b-3p (P=0.01) and miR-302b-5p (P=0.03), likely via CD44. FKBPL-based peptide mimetic, AD-01 (1 nM), in high-glucose conditions, upregulated endothelial vcam1 and glut1 mRNA expression, independent of miR-302b-5p.

Conclusions: FKBPL plays an important role in glucose metabolism, endothelial function, angiogenesis, cardiac inflammation and function, and could be explored as a therapeutic target of cardiovascular disease both in nondiabetes and diabetes settings using precision medicine approach.

Background: Time-restricted eating has gained attention for its potential cardiometabolic health benefits. Existing time-restricted eating approaches may have limited adherence and sustainability due to fixed fasting windows with prolonged fasting duration before sleep, or they involve self-selected fasting windows without specifying the duration relative to sleep, a critical period for cardiometabolic regulation. We hypothesized that an individualized approach that extended overnight fasting duration by 3 hours in alignment with habitual sleep time (last meal ≥3 hours before sleep) would enhance nighttime autonomic balance, decrease blood pressure and heart rate, increase blood pressure per hour dipping, and glucose regulation compared with a control group maintaining habitual eating patterns.

Methods: In this randomized parallel-arm controlled trial, 39 overweight/obese participants (36-75 years) completed either an extended overnight fasting intervention (13-16-hour fasting) or a control condition (habitual fast of 11-13 hours). Both groups dimmed lights 3 hours before bedtime. The intervention duration was 7.5 weeks.

Results: Compared with control, extended overnight fasting intervention significantly improved the coprimary outcome of nighttime dipping of diastolic blood pressure, but not the Matsuda Index of insulin sensitivity. extended overnight fasting improved secondary measures of nighttime autonomic function and morning oral glucose tolerance, including lower nighttime heart rate, higher heart rate variability, lower nighttime cortisol, and during the Oral Glucose Tolerance Test, lower glucose level, and higher 30-minute insulinogenic index, indicating improved acute insulin response.

Conclusions: Extending overnight fasting duration by 3 hours in alignment with sleep improved cardiometabolic health in middle-aged/older adults by strengthening coordination between circadian- and sleep-regulated autonomic and metabolic activity. This sleep-aligned time-restricted eating approach represents a novel, accessible lifestyle intervention with promising potential for improving cardiometabolic function.

Sarcoidosis is a chronic inflammatory disease of unknown cause that can affect the heart and blood vessels, causing cardiomyopathy, pulmonary hypertension, and vasculitis. The pathological hallmark of sarcoidosis is the formation of noncaseating granulomas consisting of monocytes and dendritic cells, macrophages, multinucleated giant cells, and T cells. Sarcoidosis has features of autoimmune disease, and many candidate self-epitopes have been identified, but experimental validation is lacking. There is a strong hereditary component associated with the human leukocyte antigen region on chromosome 6. Symptoms of the disease may be subtle and often go unrecognized by patients and practitioners. Catastrophic events, including sudden cardiac death caused by lethal arrhythmias, can be the initial manifestation of the disease. Diagnosis is challenging and limited by the lack of sensitive and specific diagnostic tools, which also hampers monitoring of disease activity. Here, we discuss the cardiovascular manifestations and underlying immunobiology of sarcoidosis. We also review current diagnostic and treatment approaches for cardiac sarcoidosis, as well as the challenges faced by patients and clinicians and opportunities for future research.

Adipose tissue lipid metabolism is a critical regulator of systemic energy balance, but its impact on cardiometabolic health is paradoxical. This review dissects the 2 primary lipolytic systems in adipocytes: the canonical cytosolic pathway driven by ATGL/PNPLA2 (adipose triglyceride lipase) and the lysosomal pathway governed by LAL/LIPA (lysosomal acid lipase). We present emerging evidence that these pathways exert opposing effects in the context of obesity. While excessive fatty acid efflux from dysregulated cytosolic lipolysis is a known driver of adiposopathic dyslipidemia, adipose inflammation, and direct cardiac lipotoxicity, which collectively impair cardiometabolic health, the activity of the lysosomal pathway is emerging as a protective counterbalance. Genetic and pharmacological studies demonstrate that inhibiting cytosolic ATGL is beneficial for metabolic health, whereas enhancing LAL-mediated lipolysis mitigates obesity-related dysfunction. This functional antagonism between cytosolic and lysosomal lipolysis presents a new paradigm in lipid metabolism, suggesting that therapeutic strategies must be pathway-specific. We conclude that selectively inhibiting pathogenic cytosolic lipid release while promoting beneficial lysosomal lipid processing offers a nuanced approach to treating metabolic disease.

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.