Vascular remodeling is a very general feature related to angiogenesis and arteriogenesis, which are involved in neovascularization processes [...].

Optimal vascular structure and function are essential for maintaining the physiological functions of the cardiovascular system. Vascular remodelling involves changes in vessel structure, including its size, shape, cellular and molecular composition. These changes result from multiple risk factors and may be compensatory adaptations to sustain blood vessel function. They occur in diverse cardiovascular pathologies, from hypertension to heart failure and atherosclerosis. Dynamic changes in the endothelium, fibroblasts, smooth muscle cells, pericytes or other vascular wall cells underlie remodelling. In addition, immune cells, including macrophages and lymphocytes, may infiltrate vessels and initiate inflammatory signalling. They contribute to a dynamic interplay between cell proliferation, apoptosis, migration, inflammation, and extracellular matrix reorganisation, all critical mechanisms of vascular remodelling. Molecular pathways underlying these processes include growth factors (e.g., vascular endothelial growth factor and platelet-derived growth factor), inflammatory cytokines (e.g., interleukin-1β and tumour necrosis factor-α), reactive oxygen species, and signalling pathways, such as Rho/ROCK, MAPK, and TGF-β/Smad, related to nitric oxide and superoxide biology. MicroRNAs and long noncoding RNAs are crucial epigenetic regulators of gene expression in vascular remodelling. We evaluate these pathways for potential therapeutic targeting from a clinical translational perspective. In summary, vascular remodelling, a coordinated modification of vascular structure and function, is crucial in cardiovascular disease pathology.

In the context of arteriovenous fistula (AVF) failure, local delivery enables the release of higher concentrations of drugs that can suppress neointimal hyperplasia (NIH) while reducing systemic adverse effects. However, the radiolucency of polymeric delivery systems hinders long-term in vivo surveillance of safety and efficacy. We hypothesize that using a radiopaque perivascular wrap to deliver anti-NIH drugs could enhance AVF maturation. Through electrospinning, we fabricated multifunctional perivascular polycaprolactone (PCL) wraps loaded with bismuth nanoparticles (BiNPs) for enhanced radiologic visibility and drugs that can attenuate NIH─rosuvastatin (Rosu) and rapamycin (Rapa). The following groups were tested on the AVFs of a total of 24 Sprague-Dawley rats with induced chronic kidney disease: control (i.e., without wrap), PCL-Bi (i.e., wrap with BiNPs), PCL-Bi-Rosu, and PCL-Bi-Rapa. We found that BiNPs significantly improved the wraps\' radiopacity without affecting biocompatibility. The drug release profiles of Rosu (hydrophilic drug) and Rapa (hydrophobic drug) differed significantly. Rosu demonstrated a burst release followed by gradual tapering over 8 weeks, while Rapa demonstrated a gradual release similar to that of the hydrophobic BiNPs. In vivo investigations revealed that both drug-loaded wraps can reduce vascular stenosis on ultrasonography and histomorphometry, as well as reduce [18F]Fluorodeoxyglucose uptake on positron emission tomography. Immunohistochemical studies revealed that PCL-Bi-Rosu primarily attenuated endothelial dysfunction and hypoxia in the neointimal layer, while PCL-Bi-Rapa modulated hypoxia, inflammation, and cellular proliferation across the whole outflow vein. In summary, the controlled delivery of drugs with different properties and mechanisms of action against NIH through a multifunctional, radiopaque perivascular wrap can improve imaging and histologic parameters of AVF maturation.

暂无摘要。

暂无摘要。

Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.

Discoidin, CUB, LCCL domain-containing 2 (DCBLD2) is a type I transmembrane protein with a similar structure to neuropilin, which acts as a co-receptor for certain receptor tyrosine kinases (RTKs). The insulin receptor is an RTK and plays a critical role in endothelial cell function and glycolysis. However, how and whether DCBLD2 regulates insulin receptor activity in endothelial cells is poorly understood. Diabetes was induced through treatment of Dcbld2 global-genome knockout mice and endothelium-specific knockout mice with streptozotocin. Vascular ultrasound, vascular tension test, and hematoxylin and eosin staining were performed to assess endothelial function and aortic remodeling. Glycolytic rate assays, real-time PCR and western blotting were used to investigate the effects of DCBLD2 on glycolytic activity and insulin receptor (InsR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in endothelial cells. Co-immunoprecipitation was used to assess the effects of DCBLD2 on insulin receptor endocytosis and recycling. Membrane and cytoplasmic proteins were isolated to determine whether DCBLD2 could affect the localization of the insulin receptor. We found that Dcbld2 deletion exacerbated endothelial dysfunction and vascular remodeling in diabetic mice. Both Dcbld2 knockdown and Dcbld2 deletion inhibited glycolysis and the InsR/PI3K/Akt signaling pathway in endothelial cells. Furthermore, Dcbld2 deletion inhibited insulin receptor recycling. Taken together, Dcbld2 deficiency exacerbated diabetic endothelial dysfunction and vascular remodeling by inhibiting the InsR/PI3K/Akt pathway in endothelial cells through the inhibition of Rab11-dependent insulin receptor recycling. Our data suggest that DCBLD2 is a potential therapeutic target for diabetes and cardiovascular diseases.

Pulmonary hypertension (PH) is characterized by vascular remodeling predominantly driven by a phenotypic switching in pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanisms for this phenotypic alteration remain incompletely understood. Here, we identified that RNA methyltransferase METTL3 is significantly elevated in the lungs of hypoxic PH (HPH) mice and rats, as well as in the pulmonary arteries (PAs) of HPH rats. Targeted deletion of Mettl3 in smooth muscle cells exacerbated hemodynamic consequences of hypoxia-induced PH and accelerated pulmonary vascular remodeling in vivo. Additionally, the absence of METTL3 markedly induced phenotypic switching in PASMCs in vitro. Mechanistically, METTL3 depletion attenuated m6A modification and hindered the processing of pri-miR-143/145, leading to a downregulation of miR-143-3p and miR-145-5p. Inhibition of hnRNPA2B1, an m6A mediator involved in miRNA maturation, similarly resulted in a significant reduction of miR-143-3p and miR-145-5p. We demonstrated that miR-145-5p targets Krüppel-like factor 4 (KLF4) and miR-143-3p targets fascin actin-bundling protein 1 (FSCN1) in PASMCs. The decrease of miR-145-5p subsequently induced an upregulation of KLF4, which in turn suppressed miR-143/145 transcription, establishing a positive feedback circuit between KLF4 and miR-143/145. This regulatory circuit facilitates the persistent suppression of contractile marker genes, thereby sustaining PASMC phenotypic switch. Collectively, hypoxia-induced upregulation of METTL3, along with m6A mediated regulation of miR-143/145, might serve as a protective mechanism against phenotypic switch of PASMCs. Our results highlight a potential therapeutic strategy targeting m6A modified miR-143/145-KLF4 loop in the treatment of PH.

Clinical outcomes of arteriovenous fistulae (AVF) for hemodialysis remain inadequate since biological mechanisms of AVF maturation and failure are still poorly understood. Aortocaval fistula creation (AVF group) or a sham operation (sham group) was performed in C57BL/6 mice. Venous limbs were collected on postoperative day 7 and total RNA was extracted for high throughput RNA sequencing and bioinformatic analysis. Genes in metabolic pathways were significantly downregulated in the AVF, whereas significant sex differences were not detected. Since gene expression patterns among the AVF group were heterogenous, the AVF group was divided into a \'normal\' AVF (nAVF) group and an \'outliers\' (OUT) group. The gene expression patterns of the nAVF and OUT groups were consistent with previously published data showing venous adaptive remodeling, whereas enrichment analyses showed significant upregulation of metabolism, inflammation and coagulation in the OUT group compared to the nAVF group, suggesting the heterogeneity during venous remodeling reflects early gene expression changes that may correlate with AVF maturation or failure. Early detection of these processes may be a translational strategy to predict fistula failure and reduce patient morbidity.

Pulmonary arterial hypertension (PAH), one subtype of pulmonary hypertension (PH), is a life-threatening condition characterized by pulmonary arterial remodeling, elevated pulmonary vascular resistance, and blood pressure in the pulmonary arteries, leading to right heart failure and increased mortality. The disease is marked by endothelial dysfunction, vasoconstriction, and vascular remodeling. The role of Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors, a class of medications originally developed for diabetes management, is increasingly being explored in the context of cardiovascular diseases, including PAH, due to their potential to modulate these pathophysiological processes. In this review, we systematically examine the burgeoning evidence from both basic and clinical studies that describe the effects of SGLT2 inhibitors on cardiovascular health, with a special emphasis on PAH. By delving into the complex interactions between these drugs and the potential pathobiology that underpins PH, this study seeks to uncover the mechanistic underpinnings that could justify the use of SGLT2 inhibitors as a novel therapeutic approach for PAH. We collate findings that illustrate how SGLT2 inhibitors may influence the normal function of pulmonary arteries, possibly alleviating the pathological hallmarks of PAH such as inflammation, oxidative stress, aberrant cellular proliferation, and so on. Our review thereby outlines a potential paradigm shift in PAH management, suggesting that these inhibitors could play a crucial role in modulating the disease\'s progression by targeting the potential dysfunctions that drive it. This comprehensive synthesis of existing research underscores the imperative need for further clinical trials to validate the efficacy of SGLT2 inhibitors in PAH and to integrate them into the therapeutic agents used against this challenging disease.