Search Results (926)

The tumor microenvironment (TME) can be regarded as a complex and dynamic microecosystem generated by the interactions of tumor cells, interstitial cells, the extracellular matrix, and their products and plays an important role in the occurrence, progression and metastasis of tumors. In a previous study, we constructed an IEO model (prI-, prE-, and pOst-metastatic niche) according to the chronological sequence of TME development. In this paper, to fill the theoretical gap in spatial heterogeneity in the TME, we defined an MCIB model (Metabolic, Circulatory, Immune, and microBial microenvironment). The MCIB model divides the TME into four subtypes that interact with each other in terms of mechanism, corresponding to the four major links of metabolic reprogramming, vascular remodeling, immune response, and microbial action, providing a new way to assess the TME. The combination of the MCIB model and IEO model comprehensively depicts the spatiotemporal evolution of the TME and can provide a theoretical basis for the combination of clinical targeted therapy, immunotherapy, and other comprehensive treatment modalities for tumors according to the combination and crosstalk of different subtypes in the MCIB model and provide a powerful research paradigm for tumor drug-resistance mechanisms and tumor biological behavior. Full article

Coronary aneurysms are typically defined as sections of a coronary artery where the diameter is more than 1.5 times that of an adjacent normal segment. In rare circumstances, these aneurysms can become exceedingly large, leading to the classification of giant coronary artery aneurysms. Despite their occurrence, there is no clear consensus on the precise definition of giant coronary artery aneurysms, and their etiology remains somewhat ambiguous. Numerous potential causes have been suggested, with atherosclerosis being the most prevalent in adults, accounting for up to 50% of cases. In pediatric populations, Kawasaki disease and Takayasu arteritis are the primary causes. Although often discovered incidentally, coronary artery aneurysms can lead to severe complications. These complications include local thrombosis, distal embolization, rupture, and vasospasm, which can result in ischemia, heart failure, and arrhythmias. The optimal approach to medical, interventional, or surgical management of these aneurysms is still under debate and requires further clarification. This literature review aims to consolidate current knowledge regarding coronary artery aneurysms’ pathophysiology, emphasizing their definition, causes, complications, and treatment strategies. Recent research has begun to explore the molecular mechanisms involved in the formation and progression of coronary artery aneurysms. Various molecules, such as matrix metalloproteinases (MMPs), inflammatory cytokines, and growth factors, play crucial roles in the degradation of the extracellular matrix and the remodeling of vascular walls. Elevated levels of MMPs, particularly MMP-9, have been associated with the weakening of the arterial wall, contributing to aneurysm development. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6) have been implicated in promoting inflammatory responses that further degrade vascular integrity. Additionally, growth factors such as vascular endothelial growth factor (VEGF) may influence angiogenesis and vascular remodeling processes. Understanding these molecular pathways is essential for developing targeted therapies aimed at preventing the progression of coronary artery aneurysms and improving patient outcomes. Full article

Cardiovascular disease is a leading cause of morbidity and mortality. New research elucidates increasingly complex relationships between cardiac and metabolic health, giving rise to new possible therapeutic targets. Sphingolipids are a heterogeneous class of bioactive lipids with critical roles in normal human physiology. They have also been shown to play both protective and deleterious roles in the pathogenesis of cardiovascular disease. Ceramides are implicated in dysregulating insulin signalling, vascular endothelial function, inflammation, oxidative stress, and lipoprotein aggregation, thereby promoting atherosclerosis and vascular disease. Ceramides also advance myocardial disease by enhancing pathological cardiac remodelling and cardiomyocyte death. Glucosylceramides similarly contribute to insulin resistance and vascular inflammation, thus playing a role in atherogenesis and cardiometabolic dysfunction. Sphingosing-1-phosphate, on the other hand, may ameliorate some of the pathological functions of ceramide by protecting endothelial barrier integrity and promoting cell survival. Sphingosine-1-phosphate is, however, implicated in the development of cardiac fibrosis. This review will explore the roles of sphingolipids in vascular, cardiac, and metabolic pathologies and will evaluate the therapeutic potential in targeting sphingolipids with the aim of prevention and reversal of cardiovascular disease in order to improve long-term cardiovascular outcomes. Full article

The delivery of nutrients to the brain is provided by a 600 km network of capillaries and microvessels. Indeed, the brain is highly energy demanding and, among a total amount of 100 billion neurons, each neuron is located just 10–20 μm from a capillary. This vascular network also forms part of the blood–brain barrier (BBB), which maintains the brain’s stable environment by regulating chemical balance, immune cell transport, and blocking toxins. Typically, brain microvascular endothelial cells (BMECs) have low turnover, indicating a stable cerebrovascular structure. However, this structure can adapt significantly due to development, aging, injury, or disease. Temporary neural activity changes are managed by the expansion or contraction of arterioles and capillaries. Hypoxia leads to significant remodeling of the cerebrovascular architecture and pathological changes have been documented in aging and in vascular and neurodegenerative conditions. These changes often involve BMEC proliferation and the remodeling of capillary segments, often linked with local neuronal changes and cognitive function. Cerebrovascular plasticity, especially in arterioles, capillaries, and venules, varies over different time scales in development, health, aging, and diseases. Rapid changes in cerebral blood flow (CBF) occur within seconds due to increased neural activity. Prolonged changes in vascular structure, influenced by consistent environmental factors, take weeks. Development and aging bring changes over months to years, with aging-associated plasticity often improved by exercise. Injuries cause rapid damage but can be repaired over weeks to months, while neurodegenerative diseases cause slow, varied changes over months to years. In addition, if animal models may provide useful and dynamic in vivo information about vascular plasticity, humans are more complex to investigate and the hypothesis of glymphatic system together with Magnetic Resonance Imaging (MRI) techniques could provide useful clues in the future. Full article

Adipose tissue is composed of adipocytes, stromal vascular fraction, nerves, surrounding immune cells, and the extracellular matrix. Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called “adipose tissue plasticity”. Adipose tissue plasticity includes changes in the size, species, number, lipid storage capacity, and differentiation function of adipocytes, as well as alterations in the distribution and cellular composition of adipose tissue. This plasticity has a major role in growth, obesity, organismal protection, and internal environmental homeostasis. Moreover, certain thresholds exist for this plasticity with significant individualized differences. Here, we comprehensively elaborate on the specific connotation of adipose tissue plasticity and the relationship between this plasticity and the development of many diseases. Meanwhile, we summarize possible strategies for treating obesity in response to adipose tissue plasticity, intending to provide new insights into the dynamic changes in adipose tissue and contribute new ideas to relevant clinical problems. Full article

Cardiovascular diseases, particularly ischemic heart disease, area leading cause of morbidity and mortality worldwide. Myocardial infarction (MI) results in extensive cardiomyocyte loss, inflammation, extracellular matrix (ECM) degradation, fibrosis, and ultimately, adverse ventricular remodeling associated with impaired heart function. While heart transplantation is the only definitive treatment for end-stage heart failure, donor organ scarcity necessitates the development of alternative therapies. In such cases, methods to promote endogenous tissue regeneration by stimulating growth factor secretion and vascular formation alone are insufficient. Techniques for the creation and transplantation of viable tissues are therefore highly sought after. Approaches to cardiac regeneration range from stem cell injections to epicardial patches and interposition grafts. While numerous preclinical trials have demonstrated the positive effects of tissue transplantation on vasculogenesis and functional recovery, long-term graft survival in large animal models is rare. Adequate vascularization is essential for the survival of transplanted tissues, yet pre-formed microvasculature often fails to achieve sufficient engraftment. Recent studies report success in enhancing cell survival rates in vitro via tissue perfusion. However, the transition of these techniques to in vivo models remains challenging, especially in large animals. This review aims to highlight the evolution of cardiac patch and stem cell therapies for the treatment of cardiovascular disease, identify discrepancies between in vitro and in vivo studies, and discuss critical factors for establishing effective myocardial tissue regeneration in vivo. Full article

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is relatively common, affecting up to 50% of patients with idiopathic pulmonary fibrosis (IPF). It occurs more frequently in advanced fibrotic ILD, although it may also complicate milder disease and carries significant clinical implications in terms of morbidity and mortality. Key pathological processes driving ILD-PH include hypoxic pulmonary vasoconstriction and pulmonary vascular remodelling. While current understanding of the complex cell signalling pathways and molecular mechanisms underlying ILD-PH remains incomplete, there is evidence for an interplay between the disease pathogenesis of fibrotic ILD and PH, with interest in the role of the pulmonary endothelium in driving pulmonary fibrogenesis more recently. This review examines key clinical trials in ILD-PH therapeutics, including recent research showing promise for the treatment of both ILD-PH and the underlying pulmonary fibrotic process, further supporting the hypothesis of interrelated pathogenesis. Other important management considerations are discussed, including the value of accurate phenotyping in ILD-PH and the success of the “pulmonary vascular” phenotype. This article highlights the close and interconnected nature of fibrotic ILD and PH disease pathogenesis, a perspective likely to improve our understanding and therapeutic approach to this complex condition in the future. Full article

Previous experimental findings have led to considerable interest in the beneficial effects on pulmonary hypertension (PH) produced by sildenafil and in the pleiotropic effects of rosuvastatin and their positive role in the process of pulmonary angiogenesis. However, magnesium sulfate, the most abundant intracellular cation, is essential in vascular endothelial functionality due to its anti-inflammatory and vasodilatory effects. Therefore, the present study aims to assess these treatment regimens and how they could potentially provide some additional benefits in PH therapy. Fourteen days after chronic-hypoxia PH was induced, rosuvastatin, sildenafil and magnesium sulfate were administered for an additional fourteen days to male Wistar rats. The Fulton Index, right ventricle (RV) anterior wall thickness, RV internal diameter and pulmonary arterial (PA) acceleration time/ejection time were evaluated, and another four biochemical parameters were calculated: brain natriuretic peptide, vascular endothelial growth factor, nitric oxide metabolites and endothelin 1. The present study demonstrates that sildenafil and rosuvastatin have modest effects in reducing RV hypertrophy and RV systolic pressure. The drug combination of sildenafil + rosuvastatin + magnesium sulfate recorded statistically very highly significant results on all parameters; through their positive synergistic effects on vascular endothelial function, oxidative stress and pathological RV remodeling, they attenuated PH in the chronic hypoxia pulmonary hypertension (CHPH) rat model. Full article

Chemerin, an adipokine known for its role in adipogenesis and inflammation, has emerged as a significant biomarker in cardiovascular diseases, including acute myocardial infarction (AMI). Recent studies have highlighted chemerin’s involvement in the pathophysiological processes of coronary artery disease (CAD), where it modulates inflammatory responses, endothelial function, and vascular remodelling. Elevated levels of chemerin have been associated with adverse cardiovascular outcomes, including increased myocardial injury, left ventricular dysfunction, and heightened inflammatory states post-AMI. This manuscript aims to provide a comprehensive review of the current understanding of chemerin’s role in AMI, detailing its molecular mechanisms, clinical implications, and potential as a biomarker for diagnosis and prognosis. Additionally, we explore the therapeutic prospects of targeting chemerin pathways to mitigate myocardial damage and improve clinical outcomes in AMI patients. By synthesizing the latest research findings, this review seeks to elucidate the multifaceted role of chemerin in AMI and its promise as a target for innovative therapeutic strategies. Full article

(200/200) Purpose: Our aim was to evaluate structural alterations of retinal arterioles due to type 1 diabetes (T1D) and/or diabetic retinopathy (DR) under AOSLO imaging. Methods: Each study eye underwent mydriasis and AOSLO imaging in a single-visit study. The instrument’s arrangement of four offset aperture images provided two orthogonal split-detector images and enabled isotropic analysis of the arteriolar boundaries. For each arteriole, we calculated the wall-to-lumen ratio (WLR), mean wall thickness, and luminal and external diameters. Results: In total, we enrolled 5 (20.8%) healthy control eyes and 19 eyes of patients with T1D. The DR distribution was: four (16.7%) no-DR, nine (37.5%%) mild or moderate nonproliferative DR (NPDR), and six (25%) severe NPDR or proliferative DR. Mean wall thickness increased significantly in eyes with T1D compared to healthy controls (p = 0.0006) and in eyes with more advanced DR (p = 0.0004). The WLR was significantly higher in eyes with T1D (p = 0.002) or more severe DR (p = 0.004). There was no significant relationship between T1D status or DR severity and any of the arteriolar diameters. Conclusions: In this preliminary study, there appeared to be increases in the WLR and mean wall thickness in eyes with T1D and more severe DR than in the controls and eyes with no/less severe DR. Future studies may further elucidate the relationship between the retinal arteriolar structure and physiologic alterations in DR. Full article

The significance of hypoxia at the maternal–fetal interface is proven to be self-explanatory in the context of pregnancy. During the first trimester, low oxygen conditions play a crucial role in processes such as angiogenesis, trophoblast invasion and differentiation, and immune regulation. Recently, there has been increasing research on decidual macrophages, which contribute to the maintenance of immune tolerance, placental and fetal vascular development, and spiral artery remodeling, to investigate the effects of hypoxia on their biological behaviors. On these grounds, this review describes the dynamic changes in oxygen levels at the maternal–fetal interface throughout gestation, summarizing current knowledge on how the hypoxic environment sustains a successful pregnancy by regulating retention, differentiation and efferocytosis of decidual macrophages. Additionally, we explore the relationship between spontaneous miscarriages and an abnormal hypoxia–macrophage axis, shedding light on the underlying mechanisms. However, further studies are essential to elucidate these pathways in greater detail and to develop targeted interventions that could improve pregnancy outcomes. Full article

Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB₁Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB₁Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB₁R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM–1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB₁R gene. However, with the defect of the CB₁R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, p < 0.05) but attenuated in the CB₁R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB₁R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB₁Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB₁R gene significantly attenuates vascular damage in hypercholesterolemic mice. Full article

The number of patients with end-stage renal disease (ESRD) requiring hemodialysis is increasing worldwide. Although arteriovenous fistula (AVF) is the best and most important vascular access (VA) for hemodialysis, its primary maturation failure rate is as high as 60%, which seriously endangers the prognosis of hemodialysis patients. After AVF establishment, the venous outflow tract undergoes hemodynamic changes, which are translated into intracellular signaling pathway cascades, resulting in an outward and inward remodeling of the vessel wall. Outward remodeling refers to the thickening of the vessel wall and the dilation of the lumen to accommodate the high blood flow in the AVF, while inward remodeling is mainly characterized by intimal hyperplasia. More and more studies have shown that the two types of remodeling are closely related in the occurrence and development of, and jointly determining the final fate of, AVF. Therefore, it is essential to investigate the underlying mechanisms involved in outward and inward remodeling for identifying the key targets in alleviating AVF dysfunction. In this review, we summarize the current clinical diagnosis, monitoring, and treatment techniques for AVF dysfunction and discuss the possible pathological mechanisms related to improper outward and inward remodeling in AVF dysfunction, as well as summarize the similarities and differences between the two remodeling types in molecular mechanisms. Finally, the representative therapeutic targets of potential clinical values are summarized. Full article

Hutchinson–Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder that causes accelerated aging, due to a pathogenic variant in the LMNA gene. This pathogenic results in the production of progerin, a defective protein that disrupts the nuclear lamina’s structure. In our study, we conducted a histopathological analysis of various organs in the Lmna^G609G/G609G mouse model, which is commonly used to study HGPS. The objective of this study was to show that progerin accumulation drives systemic but organ-specific tissue damage and accelerated aging phenotypes. Our findings show significant fibrosis, inflammation, and dysfunction in multiple organ systems, including the skin, cardiovascular system, muscles, lungs, liver, kidneys, spleen, thymus, and heart. Specifically, we observed severe vascular fibrosis, reduced muscle regeneration, lung tissue remodeling, depletion of fat in the liver, and disruptions in immune structures. These results underscore the systemic nature of the disease and suggest that chronic inflammation and fibrosis play crucial roles in the accelerated aging seen in HGPS. Additionally, our study highlights that each organ responds differently to the toxic effects of progerin, indicating that there are distinct mechanisms of tissue-specific damage. Full article

Acute coronary syndrome (ACS) is a complex clinical syndrome that encompasses acute myocardial infarction (AMI) and unstable angina (UA). Its underlying mechanism refers to coronary plaque disruption, with consequent platelet aggregation and thrombosis. Inflammation plays an important role in the progression of atherosclerosis by mediating the removal of necrotic tissue following myocardial infarction and shaping the repair processes that are essential for the recovery process after ACS. As a chronic inflammatory disorder, atherosclerosis is characterized by dysfunctional immune inflammation involving interactions between immune (macrophages, T lymphocytes, and monocytes) and vascular cells (endothelial cells and smooth muscle cells). New-onset atrial fibrillation (NOAF) is one of the most common arrhythmic complications in the setting of acute coronary syndromes, especially in the early stages, when the myocardial inflammatory reaction is at its maximum. The main changes in the atrial substrate are due to atrial ischemia and acute infarcts that can be attributed to neurohormonal factors. The high incidence of atrial fibrillation (AF) post-myocardial infarction may be secondary to inflammation. Inflammatory response and immune system cells have been involved in the initiation and development of atrial fibrillation. Several inflammatory indexes, such as C-reactive protein and interleukins, have been demonstrated to be predictive of prognosis in patients with ACS. The cell signaling activation patterns associated with fibrosis, apoptosis, and hypertrophy are forms of cardiac remodeling that occur at the atrial level, predisposing to AF. According to a recent study, the presence of fibrosis and lymphomononuclear infiltration in the atrial tissue was associated with a prior history of AF. However, inflammation may contribute to both the occurrence/maintenance of AF and its thromboembolic complications. Full article