Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Background: FFAR4 (free fatty acid receptor 4) has emerged as a target for preventing cardiovascular disease through its ability to control macrophage inflammation and foam cell formation. Previous studies have shown that FFAR4 activation can protect against the accumulation of arterial plaque buildup in atherosclerotic animal models. The goal of our study is to test the hypothesis that FFAR4 deficiency will increase atherosclerotic plaque development in apoE^-/- mice.

Methods: Male and female apoE^-/-/Ffar4^-/- mice and their apoE^-/- controls were fed a Western diet for 8 or 16 weeks to assess early and advanced atherosclerotic lesions, respectively. At the end of each study, atherosclerotic plaque severity was determined by analyzing the aortic sinus lesion area of the heart and the en face lesion area of the aortic arch.

Results: Following 8 weeks of Western diet feeding, lesions from apoE^-/-/Ffar4^-/- male and female mice had 33% and 22% decreases, respectively, in the aortic sinus lesion area with no changes in the aortic arch lesion area. After 16 weeks of Western diet feeding, the lesions showed no changes in the area or volume of the aortic sinus between apoE^-/-/Ffar4^-/- mice and apoE^-/- controls. However, male apoE^-/-/Ffar4^-/- mice had a 27% increase in the plaque lesion area in the aortic arch compared with apoE^-/- controls. Despite similar sizes of lesions in the aortic sinus, apoE^-/-/Ffar4^-/- mice had larger necrotic cores compared with the apoE^-/- control mice. In fact, male and female mice had 43% and 37% increases in the necrotic lesion area, respectively.

Conclusions: These data suggest a novel role for FFAR4 in reducing necrotic core lesion formation and support a protective role for FFAR4 in stabilizing atherosclerotic plaques.

Background: Cardiovascular disease is the leading cause of mortality in patients with chronic kidney disease (CKD). APOM plays a critical role in reverse cholesterol transport by facilitating the formation of pre-β-HDL (high-density lipoprotein) and enabling the binding of S1P (sphingosine-1-phosphate) to HDL, a complex involved in several antiatherogenic processes. In this study, we sought to investigate the potential association between plasma APOM levels and the risk of adverse cardiovascular outcomes in individuals with CKD.

Methods: Plasma APOM levels were quantified using a sandwich ELISA-based assay. Plasma S1P levels were measured by high-performance liquid chromatography. The primary end point was a composite of major adverse cardiovascular events (MACE) and all-cause mortality.

Results: In this secondary analysis of the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation), 463 nondialysis patients with CKD stages G2 to G4 were included. Plasma APOM levels exhibited a significant inverse association with the risk of MACE (standardized hazard ratio, 0.60 [95% CI, 0.49-0.75]; P<0.001) and all-cause mortality (standardized hazard ratio, 0.63 [95% CI, 0.48-0.83]; P<0.001). This inverse association with MACE remained robust after adjusting for established cardiovascular and renal risk factors. These findings were further corroborated in an independent cohort of 822 patients with CKD from the Copenhagen CKD study. Plasma S1P levels showed an inverse association with MACE in univariable analyses; however, this relationship lost statistical significance after multivariable adjustments.

Conclusions: Our findings demonstrate a significant association between low plasma APOM levels and an increased risk of MACE in patients with CKD. These results suggest that APOM may play a role in cardiovascular protection in this vulnerable population.

Background: The ECM (extracellular matrix) provides the microenvironmental niche sensed by resident vascular smooth muscle cells (VSMCs). Aging and disease are associated with dramatic changes in ECM composition and properties; however, their impact on VSMC phenotype remains poorly studied.

Methods: Here, we describe a novel in vitro model system that utilizes endogenous ECM to study how modifications associated with age and metabolic disease impact VSMC phenotype. ECM was synthesized using primary human VSMCs and modified during culture or after decellularization. Integrity, stiffness, and composition of the ECM was measured using superresolution microscopy, atomic force microscopy, and proteomics, respectively. VSMCs reseeded onto the modified ECM were analyzed for viability and osteogenic differentiation.

Results: ECMs produced in response to mineral stress showed extracellular vesicle-mediated hydroxyapatite deposition and sequential changes in collagen composition and ECM properties. VSMCs seeded onto the calcified ECM exhibited increased extracellular vesicle release and Runx2 (Runt-related transcription factor 2)-mediated osteogenic gene expression due to the uptake of hydroxyapatite, which led to increased reactive oxygen species and the induction of DNA damage signaling. VSMCs seeded onto the nonmineralized, senescent ECM also exhibited increased Runx2-mediated osteogenic gene expression and accelerated calcification. In contrast, glycated ECM specifically induced increased ALP (alkaline phosphatase) activity, and this was dependent on RAGE (receptor for advanced glycation end products) signaling with both ALP and RAGE receptor inhibition attenuating calcification.

Conclusions: ECM modifications associated with aging and metabolic disease can directly induce osteogenic differentiation of VSMCs via distinct mechanisms and without the need for additional stimuli. This highlights the importance of the ECM microenvironment as a key driver of phenotypic modulation acting to accelerate age-associated vascular pathologies and provides a novel model system to study the mechanisms of calcification.

The intestinal microbiota influences many host biological processes, including metabolism, intestinal barrier functions, and immune responses in the gut and distant organs. Alterations in its composition have been associated with the development of inflammatory disorders and cardiovascular diseases, including Kawasaki disease (KD). KD is an acute pediatric vasculitis of unknown etiology and the leading cause of acquired heart disease in children in the United States. The presence of gastrointestinal symptoms in the acute phase of KD has been associated with an increased risk of treatment resistance and the development of coronary artery aneurysms. Studies report alterations in fecal bacterial communities of patients with KD, characterized by the blooming of pathogenic bacteria and decreased relative abundance of short-chain fatty acid-producing bacteria. However, causality and functionality cannot be established from these observational patient cohorts of KD. This highlights the need for more advanced and rigorous studies to establish causality and functionality in both experimental models of KD vasculitis and patient cohorts. Here, we review the evidence linking an altered gut microbiota composition to the development of KD, assess the potential mechanisms involved in this process, and discuss the potential therapeutic value of these observations.

Background: Sprouting blood vessels, reaching the aimed location, and establishing the proper connections are vital for building vascular networks. Such biological processes are subject to precise molecular regulation. So far, the mechanistic insights into understanding how blood vessels grow to the correct position are limited. In particular, the guide cues and the signaling-originating cells remain elusive.

Methods: Live imaging analysis was used to observe the vascular developmental process of zebrafish. Whole-mount in situ hybridization and fluorescent in situ hybridization were used to detect the expression profiles of the genes. Single-cell sequencing analysis was conducted to identify the guiding protein and its originating cells.

Results: Taking advantage of live imaging analysis, we described a directional blood vessel migration in the vascularization process of zebrafish pectoral fins. We demonstrated that pectoral fin vessel c migrated over long distances and was anastomosed with the second pair of intersegmental vessels. Furthermore, we found the cxcl12a-cxcr4a axis specifically guided this long-distance extension of pectoral fin vessel c-intersegmental vessel, and either inhibition or overexpression of cxcl12a-cxcr4a signaling both mislead the growth of pectoral fin vessel c to ectopic areas. Finally, based on an analysis of single-cell sequencing data, we revealed that a population of monocytes expresses the Cxcl12a, which guides the migration of the vascular sprout.

Conclusions: Our study identified Cxcl12a as the signaling molecule for orchestrating the organotypic-specific long-distance migration and anastomosis of the pectoral fin vessel and the intersegmental vessels in zebrafish. We discovered a specific cluster of gata1 (globin transcription factor 1)-positive monocytes responsible for expressing Cxcl12a. The findings offer novel insights into the mechanisms underlying organotypic vascularization in vertebrates.

Background: Hyperglycemia is a major contributor to endothelial dysfunction and blood vessel damage, leading to severe diabetic microvascular complications. Despite the growing body of research on the underlying mechanisms of endothelial cell (EC) dysfunction, the available drugs based on current knowledge fall short of effectively alleviating these complications. Therefore, our endeavor to explore novel insights into the cellular and molecular mechanisms of endothelial dysfunction is crucial for the field.

Methods: In this study, we performed a high-resolution imaging and time-lapse imaging analysis of the behavior of ECs in Tg(kdrl:ras-mCherry::fli1a:nGFP) zebrafish embryos upon high glucose treatment. Genetic manipulation and chemical biology approaches were utilized to analyze the underlying mechanism of high glucose-induced nuclei aggregation and aberrant migration of zebrafish ECs and cultured human ECs. Bioinformatical analysis of single-cell RNA-sequencing data and molecular biological techniques was performed to identify the target genes of foxo1a.

Results: In this study, we observed that the high glucose treatment resulted in nuclei aggregation of ECs in zebrafish intersegmental vessels. Additionally, the aberrant migration of microvascular ECs in high glucose-treated embryos, which might be a cause of nuclei aggregation, was discovered. High glucose induced aggregation of vascular endothelial nuclei via foxo1a downregulation in zebrafish embryos. Then, we revealed that high glucose resulted in the downregulation of foxo1a expression and increased the expression of its direct downstream effector, klf2a, through which the aberrant migration and aggregation of vascular endothelial nuclei were caused.

Conclusions: High glucose treatment caused the nuclei of ECs to aggregate in vivo, which resembles the crowded nuclei of ECs in microaneurysms. High glucose suppresses foxo1a expression and increases the expression of its downstream effector, klf2a, thereby causing the aberrant migration and aggregation of vascular endothelial nuclei. Our findings provide a novel insight into the mechanism of microvascular complications in hyperglycemia.

Background: Marfan syndrome (MFS) is an inherited disorder caused by mutations in the FBN1 gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined.

Methods: To elucidate the role of endothelial XOR (xanthine oxidoreductase)-derived reactive oxygen species in aortic aneurysm progression, we inhibited in vivo function of XOR either by endothelial cell (EC)-specific disruption of the Xdh gene or by systemic administration of an XOR inhibitor febuxostat in MFS mice harboring the Fbn1 missense mutation p.(Cys1041Gly). We assessed the aberrant activation of mechanosensitive signaling in the ascending aorta of Fbn1^C1041G/+ mice. Further analysis of human aortic ECs investigated the mechanisms by which mechanical stress upregulates XOR expression.

Results: We found a significant increase in reactive oxygen species generation in the ascending aorta of patients with MFS and Fbn1^C1041G/+ mice, which was associated with a significant increase in protein expression and enzymatic activity of XOR protein in aortic ECs. Genetic disruption of Xdh in ECs or treatment with febuxostat significantly suppressed aortic aneurysm progression and improved perivascular infiltration of macrophages. Mechanistically, mechanosensitive signaling involving FAK (focal adhesion kinase)-p38 MAPK (p38 mitogen-activated protein kinase) and Egr-1 (early growth response-1) was aberrantly activated in the ascending aorta of Fbn1^C1041G/+ mice, and mechanical stress on human aortic ECs upregulated XOR expression through Egr-1 upregulation. Consistently, EC-specific knockout of XOR or systemic administration of febuxostat in Fbn1^C1041G/+ mice suppressed reactive oxygen species generation, FAK-p38 MAPK activation, and Egr-1 upregulation.

Conclusions: Aberrant activation of mechanosensitive signaling in vascular ECs triggered endothelial XOR activation and reactive oxygen species generation, which contributes to the progression of aortic aneurysms in MFS. These findings highlight a drug repositioning approach using a uric acid-lowering drug febuxostat as a potential therapy for MFS.