Emerging understandings of the role of exosomes in atherosclerosis.

Atherosclerosis remains a major contributor to cardiovascular disease, the leading cause of global morbidity and mortality. Despite the elucidation of several molecular, biochemical, and cellular aspects that contribute to the etio-pathogenesis of atherosclerosis, much remains to be understood about the onset and progression of this disease. Emerging evidence supports a role for exosomes in the cellular basis of atherosclerosis. Indeed, exosomes of activated monocytes seem to accentuate a positive feedback loop that promotes recruitment of pro-inflammatory leukocytes. Moreover, in addition to their role in promoting proliferation and invasion of vascular smooth muscle cells, exosomes can also induce neovascularization within lesions and increase endothelial permeability, two important features of fibrous plaques. Depending on their sources and cargo, exosomes can also induce clot formation and contribute to other hallmarks of atherosclerosis. Taken together, it is becoming increasingly evident that a better understanding of exosome biology is integral to elucidating the pathogenesis of atherosclerosis, and may thus provide insight into a potentially new therapeutic target for this disease.

Cellular communication network factor 2 regulates smooth muscle cell transdifferentiation and lipid accumulation in atherosclerosis.

AIMS: Accruing evidence illustrates an emerging paradigm of dynamic vascular smooth muscle cell (SMC) transdifferentiation during atherosclerosis progression. However, the molecular regulators that govern SMC phenotype diversification remain poorly defined. This study aims to elucidate the functional role and underlying mechanisms of cellular communication network factor 2 (CCN2), a matricellular protein, in regulating SMC plasticity in the context of atherosclerosis. METHODS AND RESULTS: In both human and murine atherosclerosis, an up-regulation of CCN2 is observed in transdifferentiated SMCs. Using an inducible murine SMC CCN2 deletion model, we demonstrate that SMC-specific CCN2 knockout mice are hypersusceptible to atherosclerosis development as evidenced by a profound increase in lipid-rich plaques along the entire aorta. Single-cell RNA sequencing studies reveal that SMC deficiency of CCN2 positively regulates machinery involved in endoplasmic reticulum stress, endocytosis, and lipid accumulation in transdifferentiated macrophage-like SMCs during the progression of atherosclerosis, findings recapitulated in CCN2-deficient human aortic SMCs. CONCLUSION: Our studies illuminate an unanticipated protective role of SMC-CCN2 against atherosclerosis. Disruption of vascular wall homeostasis resulting from vascular SMC CCN2 deficiency predisposes mice to atherosclerosis development and progression.

In vitro evidence that the vasorelaxant effects of 2-nitro-1-phenyl-1-propanol on rat coronary arteries involve cyclic nucleotide pathways.

The synthetic nitro-alcohol 2-nitro-1-phenyl-1-propanol (NPP) has endothelium-independent relaxing properties in isolated preparations of rat aorta and mesenteric artery. In this study, we investigated whether the vasodilator effects occur in coronary vessels and explored whether hyperpolarization is involved in the underlying mechanism of NPP-induced smooth muscle relaxation. The relaxing responses were studied in isolated preparations of the left anterior descending coronary (ADC) and the septal coronary (SC) arteries, which had been previously maintained under sustained contraction induced by the thromboxane A2 analogue U-46619. Administered cumulatively, NPP elicited concentration-dependent vasorelaxation with similar potency in both vessels. The relaxant effect remained unaffected by the nitric oxide synthase inhibitor L-NAME, the protein kinase C inhibitor bisindolylmaleimide IV and the Rho-associated protein kinase inhibitor Y-27632. However, it was significantly diminished by the adenylyl cyclase inhibitor MDL-12,330A, the guanylyl cyclase inhibitor ODQ, as well as the K+ channel inhibitors tetraethylammonium and CsCl. In ADC preparations impaled with intracellular micropipettes, NPP hyperpolarized the vascular preparation. When the isolated preparation was precontracted by 5-hydroxytryptamine or 80 mM KCl, NPP-induced relaxation with lower pharmacological potency compared to the vessels contracted by U-46619. In conclusion, NPP exhibits vasorelaxant effects on rat coronary arteries, likely involving pathways that include cyclic nucleotide production and membrane hyperpolarization.

Porphyromonas gingivalis GroEL accelerates abdominal aortic aneurysm formation by matrix metalloproteinase-2 SUMOylation in vascular smooth muscle cells: A novel finding for the activation of MMP-2.

Infection is a known cause of abdominal aortic aneurysm (AAA), and matrix metalloproteases-2 (MMP-2) secreted by vascular smooth muscle cells (SMCs) plays a key role in the structural disruption of the middle layer of the arteries during AAA progression. The periodontal pathogen Porphyromonas gingivalis is highly associated with the progression of periodontitis. GroEL protein of periodontal pathogens is an important virulence factor that can invade the body through either the bloodstream or digestive tract and is associated with numerous systemic diseases. Although P. gingivalis aggravates AAA by increasing the expression of MMP-2 in animal studies, the molecular mechanism through which P. gingivalis regulates the expression of MMP-2 is still unknown and requires further investigation. In this study, we first confirmed through animal experiments that P. gingivalis GroEL promotes MMP-2 secretion from vascular SMCs, thereby aggravating Ang II-induced aortic remodeling and AAA formation. In addition, rat vascular SMCs and A7r5 cells were used to investigate the underlying mechanisms in vitro. The results demonstrated that GroEL can promote the interaction between the K639 site of MMP-2 and SUMO-1, leading to MMP-2 SUMOylation, which inhibits the reoccurrence of non-K639-mediated monoubiquitylation. Hence, the monoubiquitylation-mediated lysosomal degradation of MMP-2 is inhibited, consequently promoting MMP-2 stability and production. SUMOylation may facilitate intra-endoplasmic reticulum (ER) and Golgi trafficking of MMP-2, thereby enhancing its transport capacity. In conclusion, this is the first report demonstrating the presence of a novel posttranslational modification, SUMOylation, in the MMP family, suggesting that P. gingivalis GroEL may exacerbate AAA formation by increasing MMP-2 production through SUMOylation in vascular SMCs. This study also provides a novel perspective on the role of SUMOylation in MMP-2-induced systemic diseases.

Aerobic Exercise Prevents High-Fat-Diet-Induced Adipose Tissue Dysfunction in Male Mice.

BACKGROUND/OBJECTIVES: This study aimed to assess the effect of aerobic exercise on capillary density and vascular smooth muscle cell (VSMC) phenotype in the visceral and subcutaneous adipose tissue of high-fat-diet (HFD) mice in order to understand the mechanisms underlying improvements in insulin resistance (IR) and chronic inflammation in adipose tissue (AT). METHODS: Male C57BL/6J mice were divided into HFD and normal diet groups for 12 weeks and then further split into sedentary and aerobic exercise subgroups for an additional 8 weeks. Various parameters including body weight, fat weight, blood glucose, lipid profile, insulin levels, glucose tolerance, and inflammatory cytokines were evaluated. RESULTS: Aerobic exercise reduced HFD-induced weight gain, IR, and improved lipid profiles. HFD had a minimal effect on inflammatory cytokines except in visceral adipose tissue (VAT). IR was associated with capillary density in subcutaneous adipose tissue (SAT) and VSMC phenotype in VAT. Aerobic exercise promoted anti-inflammatory responses in VAT, correlating with VSMC phenotype in this tissue. CONCLUSIONS: Aerobic exercise can alleviate HFD-induced IR and inflammation through the modulation of VSMC phenotype in AT.

NAT10 promotes vascular remodelling via mRNA ac4C acetylation.

BACKGROUND AND AIMS: Vascular smooth muscle cell (VSMC) phenotype switching is a pathological hallmark in various cardiovascular diseases. N4-acetylcytidine (ac4C) catalyzed by N-acetyltransferase 10 (NAT10) is well conserved in the enzymatic modification of ribonucleic acid (RNA). NAT10-mediated ac4C acetylation is involved in various physiological and pathological processes, including cardiac remodelling. However, the biological functions and underlying regulatory mechanisms of mRNA ac4C modifications in vascular diseases remain elusive. METHODS: By combining in-vitro and in-vivo vascular injury models, NAT10 was identified as a crucial protein involved in the promotion of post-injury neointima formation, as well as VSMC phenotype switching. The potential mechanisms of NAT10 in the vascular neointima formation were clarified by RNA sequence (RNA-seq), acetylated mRNA immunoprecipitation sequence (acRIP-seq), and RNA binding protein immunoprecipitation sequence (RIP-seq). RESULTS: NAT10 and ac4C modifications were upregulated in injured human and rodent arteries. Deletion of NAT10 in VSMCs effectively reduced post-injury neointima formation and VSMC phenotype switching. Further RNA-seq, RIP-seq, and acRIP-seq revealed that NAT10, by its ac4C modification, directly interacts with genes, including integrin-ß1 (ITGB1) and collagen type I alpha 2 chain (Col1a2) mRNAs. Taking ITGB1 as one example, it showed that NAT10-mediated ac4C consequently increased ITGB1 mRNA stability and its downstream focal adhesion kinase (FAK) signaling, directly influencing the proliferation of VSMCs and vascular remodelling. The regulation of NAT10 on the VSMC phenotype is of translational significance because the administration of Remodelin, a NAT10 inhibitor, effectively prevents neointima formation by suppressing VSMC proliferation and downregulating ITGB1 expression and deactivating its FAK signaling. CONCLUSIONS: This study reveals that NAT10 promotes vascular remodelling via mRNA ac4C acetylation, which may be a promising therapeutic target against vascular remodelling.

Rats Exposed to Excess Sucrose During a Critical Period Develop Inflammation and Express a Secretory Phenotype of Vascular Smooth Muscle Cells.

BACKGROUND: Neonatal rats that receive sucrose during a critical postnatal period (CP, days 12 to 28) develop hypertension by the time they reach adulthood. Inflammation might contribute to changes during this period and could be associated with variations in the vascular smooth muscle (VSMC) phenotype. OBJECTIVE: We studied changes in inflammatory pathways that could underlie the expression of the secretory phenotype in the VSMC in the thoracic aorta of rats that received sucrose during CP. METHODS: We analyzed histological changes in the aorta and the expression of the COX-2, TLR4, iNOS, eNOS, MMP-2 and -9, and ß- and α-actin, the quantities of TNF-α, IL-6, and IL-1ß using ELISA, and the levels of fatty acids using gas chromatography. RESULTS: The aortic wall presented disorganization, decellularization, and wavy elastic fibers and an increase in the lumen area. The α- and ß-actin expressions were decreased, while COX-2, TLR4, TNF-α, and the activity of IL-6 were increased. Oleic acid was increased in CP in comparison to the control group. CONCLUSIONS: There is transient hypertension at the end of the CP that is accompanied by inflammation and a change in the phenotype of VSMC to the secretory phenotype. The inflammatory changes could act as epigenetic signals to determine the development of hypertension when animals reach adulthood.

TLR4 promotes smooth muscle cell-derived foam cells formation by inducing receptor-independent macropinocytosis.

Foam cells are primarily formed through scavenger receptors that mediate the uptake of various modified low-density lipoproteins (LDL) into cells. In addition to the receptor-dependent pathway, macropinocytosis is an essential non-receptor endocytic pathway for vascular smooth muscle cells (VSMCs) to take up lipids. However, the molecular mechanisms underlying this process remain unclear. Primary cultured VSMCs were stimulated with 200 ng/ml lipopolysaccharide (LPS) and 200 µg/ml native LDL (nLDL). We observed a significant increase in TLR4 protein expression and a significant activation of macropinocytosis, which correlated with the highest uptake of nLDL and intracellular lipid deposition in WT VSMCs. However, macropinocytosis was inhibited and lipid accumulation decreased after treatment with macropinocytosis inhibitors and Syk inhibitors in WT VSMCs. Consistently, TLR4 knockout significantly suppressed macropinocytosis and lipid droplets accumulation in VSMCs. Taken together, our findings suggest a critical role of TLR4/Syk signaling in promoting receptor-independent macropinocytosis leading to VSMC-derived foam cells formation.

Potential effects of a human milk oligosaccharide 6'-sialyllactose on angiotensin II-induced aortic aneurysm via p90RSK/TGF-ß/SMAD2 signaling pathway.

The aberrant phenotypic transformation of vascular smooth muscle cells (VSMCs) is a key factor in the formation of aortic aneurysm (AA). This study aimed to explore the effects of 6'-sialyllactose (6'-SL), a human milk oligosaccharide, on angiotensin II (Ang II)-induced VSMC dysfunction and AA formation both in vitro and in vivo. An AA model was established in male C57BL/6 mice challenged with Ang II via osmotic pumps and a lysyl oxidase inhibitor, ß-aminopropionitrile (BAPN), in drinking water. The mice were administered with 6'-SL, FMK (a p90RSK inhibitor), or losartan (as a positive control). In vitro, VSMCs were pretreated with 6'-SL before Ang II stimulation. We found that p90RSK inhibition abolished Ang II/BAPN-induced thoracic AA and abdominal AA formation. Treatment with 100 mg/kg 6'-SL significantly attenuated Ang II/BAPN-induced aortic dilatation. 6'-SL attenuated Ang II-induced collagen deposition, calcification, and immune cell accumulation. Consistently, 6'-SL downregulated p-p90RSK, p90RSK, and p-SMAD2, and mitigated VSMC contractility loss, as indicated by α-SMA expression in vivo. Interestingly, Ang II-induced transforming growth factor-beta (TGF-ß) signaling pathway was suppressed by p90RSK inhibition in VSMCs. 6'-SL treatment significantly reduced TGF-ß/SMAD2 targets, including dedifferentiation markers such as osteopontin and vimentin, and elastin degradation factors MMP2 and MMP9. Overexpression of p90RSK in VSMCs enhanced TGF-ß and abrogated the effects of 6'-SL. Furthermore, 6'-SL co-treatment abolished high phosphate-induced calcification in vitro via p90RSK/TGF-ß signaling pathway. Altogether, our findings suggest that 6'-SL could be a potential therapeutic candidate for protecting against Ang II-induced AA formation by inhibiting the p90RSK/TGF-ß/SMAD2 signaling pathway.

The Intersection of HIV and Pulmonary Vascular Health: From HIV Evolution to Vascular Cell Types to Disease Mechanisms.

People living with HIV (PLWH) face a growing burden of chronic diseases, owing to the combinations of aging, environmental triggers, lifestyle choices, and virus-induced chronic inflammation. The rising incidence of pulmonary vascular diseases represents a major concern for PLWH. The study of HIV-associated pulmonary vascular complications ideally requires a strong understanding of pulmonary vascular cell biology and HIV pathogenesis at the molecular level for effective applications in infectious diseases and vascular medicine. Active HIV infection and/or HIV proteins disturb the delicate balance between vascular tone and constriction, which is pivotal for maintaining pulmonary vascular health. One of the defining features of HIV is its high genetic diversity owing to several factors including its high mutation rate, recombination between viral strains, immune selective pressures, or even geographical factors. The intrinsic HIV genetic diversity has several important implications for pathogenic outcomes of infection and the overall battle to combat HIV. Challenges in the field present themselves from two sides of the same coin: those imposed by the virus itself and those stemming from the host. The field may be advanced by further developing in vivo and in vitro models that are well described for both pulmonary vascular diseases and HIV for mechanistic studies. In essence, the study of HIV-associated pulmonary vascular complications requires a multidisciplinary approach, drawing upon insights from both infectious diseases and vascular medicine. In this review article, we discuss the fundamentals of HIV virology and their impact on pulmonary disease, aiming to enhance the understanding of either area or both simultaneously. Bridging the gap between preclinical research findings and clinical practice is essential for improving patient care. Addressing these knowledge gaps requires interdisciplinary collaborations, innovative research approaches, and dedicated efforts to prioritize HIV-related pulmonary complications on the global research agenda.

3D-printing hydrogel programmed released exosomes to restore aortic medial degeneration through inhibiting VSMC ferroptosis in aortic dissection.

Aortic dissection (AD) is a devastating disease with a high mortality rate. Exosomes derived from mesenchymal stem cells (exo-MSCs) offer a promising strategy to restore aortic medial degeneration and combat ferroptosis in AD. However, their rapid degradation in the circulatory system and low treatment efficiency limit their clinical application. Methylacrylated gelatin (Gelma) was reported as a matrix material to achieve controlled release of exosomes. Herein, exo-MSCs-embedded in Gelma hydrogels (Gelma-exos) using ultraviolet light and three-dimensional (3D) printing technology. These Gelma-exos provide a sustained release of exo-MSCs as Gelma gradually degrades, helping to restore aortic medial degeneration and prevent ferroptosis. The sustained release of exosomes can inhibit the phenotypic switch of vascular smooth muscle cells (VSMCs) to a proliferative state, and curb their proliferation and migration. Additionally, the 3D-printed Gelma-exos demonstrated the ability to inhibit ferroptosis in vitro, in vivo and ex vivo experiments. In conclusion, our Gelma-exos, combined with 3D-printed technology, offer an alternative treatment approach for repairing aortic medial degeneration and ferroptosis in AD, potentially reducing the incidence of aortic dissection rupture.

Excessive collagen fiber deposition in idiopathic scrotal calcinosis: a case report.

BACKGROUND: Idiopathic scrotal calcinosis (ISC) is a manifestation of idiopathic calcinosis cutis, and its etiology is still unknown. CASE PRESENTATION: We report a 36-year-old patient manifested multiple gradually increasing yellowish-white scrotal nodules with occasional itching and stinging in the past 6 years and was successfully cured via surgical excision. The laboratory test combined with pathological analysis confirmed the diagnosis of ISC. Like pathological calcinosis in other soft tissues, a large amount of collagen fiber deposition was observed around the calcification nodule, suggesting that abnormal collagen fiber deposition might be an important factor leading to idiopathic calcinosis in the scrotum. Moreover, koilocytes, which indicate human papillomavirus (HPV) infection, were also detected around calcified nodules, indicating the potential pathogenic role of HPV infection in ISC. CONCLUSIONS: Here, we report that ISC shows abnormal excessive deposition of collagen fibers around calcified nodules, which may be a vital factor contributing to the disease. Furthermore, combined with the literature review, a new pathogenic mechanism of ISC is proposed, and the site specificity of scrotal calcinosis is explained, providing a basis for further exploration of the pathogenic mechanism of ISC.

3D Bioprinting Highly Elastic PEG-PCL-DA Hydrogel for Soft Tissue Fabrication and Biomechanical Stimulation.

3-D bioprinting is a promising technology to fabricate custom geometries for tissue engineering. However, most bioprintable hydrogels are weak and fragile, difficult to handle and cannot mimetic the mechanical behaviors of the native soft elastic tissues. We have developed a visible light crosslinked, single-network, elastic and biocompatible hydrogel system based on an acrylated triblock copolymer of poly(ethylene glycol) PEG and polycaprolactone (PCL) (PEG-PCL-DA). To enable its application in bioprinting of soft tissues, we have modified the hydrogel system on its printability and biodegradability. Furthermore, we hypothesize that this elastic material can better transmit pulsatile forces to cells, leading to enhanced cellular response under mechanical stimulation. This central hypothesis was tested using vascular conduits with smooth muscle cells (SMCs) cultured under pulsatile forces in a custom-made bioreactor. The results showed that vascular conduits made of PEG-PCL-DA hydrogel faithfully recapitulate the rapid stretch and recoil under the pulsatile pressure from 1 to 3 Hz frequency, which induced a contractile SMC phenotype, consistently upregulated the core contractile transcription factors. In summary, our work demonstrates the potential of elastic hydrogel for 3D bioprinting of soft tissues by fine tuning the printability, biodegradability, while possess robust elastic property suitable for manual handling and biomechanical stimulation.

Endothelial cells derived extracellular vesicles promote diabetic arterial calcification via circ_0008362/miR-1251-5p/Runx2 axial.

INTRODUCTION: Arterial calcification, an independent predictor of cardiovascular events, increases morbidity and mortality in patients with diabetes mellitus (DM), but its mechanisms remain unclear. Extracellular vesicles (EVs) play an important role in intercellular communication. The study investigates the role and potential mechanisms of EVs derived from endothelial cells (ECs) in regulating vascular smooth muscle cell (VSMC) calcification under high glucose (HG) condition, with a goal of developing effective prevention and treatment strategies for diabetic arterial calcification. RESULTS: The results showed that EVs derived from HG induced ECs (ECHG-EVs) exhibited a bilayer structure morphology with a mean diameter of 74.08 ± 31.78 nm, expressing EVs markers including CD9, CD63 and TSG101, but not express calnexin. ECHG-EVs was internalized by VSMCs and induced VSMC calcification by increasing Runx2 expression and mineralized nodule formation. The circ_0008362 was enriched in ECHG-EVs, and it can be transmitted to VSMCs to promote VSMC calcification both in vitro and in vivo. Mechanistically, miR-1251-5p might be one of the targets of circ_0008362 and they were co-localization in the cytoplasm of VSMCs. Runx2 was identified as the downstream target of miR-1251-5p, and circ_0008362 acted as a sponge, enhancing Runx2 expression and then promoted VSMC calcification. Besides, circ_0008362 could directly interact with Runx2 to aggravate VSMC calcification. Notably, DiR-labelled ECHG-EVs was detected in the vessels of mice. Meanwhile, the level of circ_0008362 and Runx2 were increased significantly, while the expression of miR-1251-5p was decreased significantly in calcified artery tissues of mice. However, inhibiting the release of EVs by GW4869 attenuated arterial calcification in diabetic mice. Finally, the level of circulation of plasma EVs circ_0008362 was significantly higher in patients with DM compared with normal controls. Elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. CONCLUSIONS: Our findings suggested that circ_0008362 was enriched in EVs derived from ECs and promoted VSMC calcification under HG conditions, both by sponging miR-1251-5p to upregulate Runx2 expression and through direct interaction with Runx2. Furthermore, elevated levels of plasma EVs circ_0008362 were associated with more severe coronary and aorta artery calcification in patients with DM. These results may serve as a potential prevention and therapeutic target for diabetic arterial calcification.

Vascular smooth muscle cells can be circumferentially aligned inside a channel using tunable gelatin microribbons.

The gold standard to measure arterial health is vasodilation in response to nitric oxide (NO). Vasodilation is generally measured via pressure myography of arteries isolated from animal models. However, animal arteries can be difficult to obtain and may have limited relevance to human physiology. It is, therefore, critical to engineer human cell-based arterial models capable of contraction. Vascular smooth muscle cells (SMCs) must be circumferentially aligned around the vessel lumen to contract the vessel, which is challenging to achieve in a soft blood vessel model. In this study, we used gelatin microribbons to circumferentially align SMCs inside a hydrogel channel. To accomplish this, we created tunable gelatin microribbons of varying stiffnesses and thicknesses and assessed how SMCs aligned along them. We then wrapped soft, thick microribbons around a needle and encapsulated them in a gelatin methacryloyl hydrogel, forming a microribbon-lined channel. Finally, we seeded SMCs inside the channel and showed that they adhered best to fibronectin and circumferentially aligned in response to the microribbons. Together, these data show that tunable gelatin microribbons can be used to circumferentially align SMCs inside a channel. This technique can be used to create a human artery-on-a-chip to assess vasodilation via pressure myography, as well as to align other cell types for 3D in vitro models.

Qianyang Yuyin granules alleviate hypertension-induced vascular remodeling by inhibiting the phenotypic switch of vascular smooth muscle cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Qianyang Yuyin granules (QYYY) have been used clinically to treat hypertension for over two decades. Previous clinical trials have shown that QYYY can improve vascular elastic function in hypertensive patients. However, the underlying pharmacological mechanism is unclear. AIM OF THE STUDY: To elucidate the effects and mechanisms of QYYY on vascular remodeling using a multidisciplinary approach that includes network pharmacology, proteomics, and both in vitro and in vivo experiments. MATERIALS AND METHODS: The main components of QYYY were identified using ultra-high-performance liquid chromatography and high-resolution mass spectrometry. Network pharmacology and molecular docking were employed to predict QYYY's primary active ingredients, potential therapeutic targets and intervention pathways in hypertensive vascular remodeling. We induced hypertension in male C57BL/6 mice by infusing angiotensin II (Ang II) via osmotic minipumps, and performed pre-treatment with QYYY or Sacubitril/valsartan (Entresto). Blood pressure was monitored in vivo, followed by the extraction of aortas to examine pathological structural changes and alterations in protein expression patterns. The expression and location of proteins involved in the HIF-1α/TWIST1/P-p65 signaling pathway were investigated, as well as markers of vascular smooth muscle cells (VSMCs) phenotypic switch. In vitro, we studied the effects of QYYY water extract on Ang II-stimulated human aortic VSMCs. We investigated whether QYYY could affect the HIF-1α/TWIST1/P-p65 signaling pathway, thereby ameliorating apoptosis, autophagy, and phenotype switch in VSMCs. RESULTS: We identified 62 main compounds in QYYY, combined with network pharmacology, speculated 827 potentially active substances, and explored 1021 therapeutic targets. The KEGG pathway analysis revealed that the mechanisms of action associated with QYYY therapy potentially encompass various biological processes, including metabolic pathways, TNF signaling pathways, apoptosis, Ras signaling pathways, HIF-1 signaling pathways, autophagy-animal pathways. In hypertensive mice, QYYY restored abnormally elevated blood pressure, vascular remodeling, and inflammation with a dose-response relationship while altering abnormal protein patterns. In vitro, QYYY could inhibit abnormal proliferation, migration, intracellular Ca2+ accumulation and cytoskeletal changes of VSMCs. It improved mitochondrial function, reduced ROS levels, stabilized membrane potential, prevented cell death, and reduced overproduction of TGF-ß1, TNF-a, and IL-1ß. CONCLUSION: QYYY may be able to inhibit the overactivation of the HIF-1α/TWIST1/P-p65 signaling pathway, improve the phenotypic switch, and balance apoptosis and autophagy in VSMCs, thereby effectively improving vascular remodeling caused by hypertension.

The Role of Cardio-Renal Inflammation in Deciding the Fate of the Arteriovenous Fistula in Haemodialysis Therapy.

Vascular access is an indispensable component of haemodialysis therapy for end-stage kidney disease patients. The arteriovenous fistula (AVF) is most common, but importantly, two-year failure rates are greater than fifty percent. AVF failure can occur due to a lack of suitable vascular remodelling, and inappropriate inflammation preventing maturation, or alternatively neointimal hyperplasia and vascular stenosis preventing long-term use. A comprehensive mechanistic understanding of these processes is still lacking, but recent studies highlight an essential role for inflammation from uraemia and the AVF itself. Inflammation affects each cell in the cascade of AVF failure, the endothelium, the infiltrating immune cells, and the vascular smooth muscle cells. This review examines the role of inflammation in each cell step by step and the influence on AVF failure. Inflammation resulting in AVF failure occurs initially via changes in endothelial cell activation, permeability, and vasoprotective chemokine secretion. Resultingly, immune cells can extravasate into the subendothelial space to release inflammatory cytokines and cause other deleterious changes to the microenvironment. Finally, all these changes modify vascular smooth muscle cell function, resulting in excessive and unchecked hyperplasia and proliferation, eventually leading to stenosis and the failure of the AVF. Finally, the emerging therapeutic options based off these findings are discussed, including mesenchymal stem cells, small-molecule inhibitors, and far-infrared therapies. Recent years have clearly demonstrated a vital role for inflammation in deciding the fate of the AVF, and future works must be centred on this to develop therapies for a hitherto unacceptably underserved patient population.

The Effect of Retinoids in Vascular Smooth Muscle Cells: From Phenotyping Switching to Proliferation and Migration.

Atherosclerosis, a term derived from the Greek "athero" (atheroma) and "sclerosis" (hardening), is a long-standing process that leads to the formation of atheromatous plaques in the arterial wall, contributing to the development of atherosclerotic cardiovascular disease. The proliferation and migration of vascular smooth muscle cells (VSMCs) and the switching of their phenotype play a crucial role in the whole process. Retinoic acid (RA), a natural derivative of vitamin A, has been used in the treatment of various inflammatory diseases and cell proliferation disorders. Numerous studies have demonstrated that RA has an important inhibitory effect on the proliferation, migration, and dedifferentiation of vascular smooth muscle cells, leading to a significant reduction in atherosclerotic lesions. In this review article, we explore the effects of RA on the pathogenesis of atherosclerosis, focusing on its regulatory action in VSMCs and its role in the phenotypic switching, proliferation, and migration of VSMCs. Despite the potential impact that RA may have on the process of atherosclerosis, further studies are required to examine its safety and efficacy in clinical practice.

Histone deacetylases: Regulation of vascular homeostasis via endothelial cells and vascular smooth muscle cells and the role in vascular pathogenesis.

Histone deacetylases (HDACs) are proteases that play a key role in chromosome structural modification and gene expression regulation, and the involvement of HDACs in cancer, the nervous system, and the metabolic and immune system has been well reviewed. Our understanding of the function of HDACs in the vascular system has recently progressed, and a significant variety of HDAC inhibitors have been shown to be effective in the treatment of vascular diseases. However, few reviews have focused on the role of HDACs in the vascular system. In this study, the role of HDACs in the regulation of the vascular system mainly involving endothelial cells and vascular smooth muscle cells was discussed based on recent updates, and the role of HDACs in different vascular pathogenesis was summarized as well. Furthermore, the therapeutic effects and prospects of HDAC inhibitors were also addressed in this review.

Breaking New Ground: Unraveling the USP1/ID3/E12/P21 Axis in Vascular Calcification.

Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3's interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets.