The interaction between metabolic reprogramming and key signaling pathways is required for vascular smooth muscle cells (VSMCs) phenotypic transitions and the development of disease. In response to pathological stimuli, VSMCs experience metabolic reprogramming to meet their increased energy demands and biomass synthesis. Metabolite-derived post translational modifications (PTMs) act as a key player in linking metabolic reprogramming to the VSMC phenotypic transitions. The alteration of metabolites of glucose, lipids and amino acids in the microenvironment also governs key signaling pathways via PTMs in VSMCs. Here, we introduce the basic processes of metabolite-derived PTMs, including phosphorylation, succinylation, acetylation, lactylation, O-GlcNAcylation, palmitoylation, crotonylation, methylation, serotonylation and glutamylation, emphasize the importance of cross talk of PTMs and summarize the underlying mechanisms of metabolite-derived PTMs in regulating the VSMC phenotypic transitions.

Population aging is changing the needs of patients seen in cardio-oncology. Older adults with cancer often have cardiovascular disease, multimorbidity, and reduced physiological reserve, which can complicate treatment and recovery. Patients of the same chronological age may differ considerably in cardiovascular health, functional capacity, and treatment tolerance. Frailty and geriatric assessment can help characterize these differences and inform care. This review examines the biological mechanisms linking aging, cancer, and cardiovascular disease and discusses their implications for cardiovascular risk assessment, cancer treatment decisions, and long-term survivorship. Treatment decisions require consideration of the expected oncological benefit, cardiovascular risk, physiological reserve, life expectancy, and patient preferences. Identifying and addressing reversible vulnerabilities may help patients tolerate effective anticancer therapy while preserving function and quality of life. During survivorship, cardiovascular care should account for previous treatment exposure, changing health status, and adherence to preventive therapies. Closer collaboration between cardio-oncology and geriatric medicine may improve the assessment and management of older patients. Evidence specific to frail and very old adults remains limited. Prospective studies are needed to determine whether geriatric and biological aging measures improve cardiovascular risk prediction, treatment decisions, and patient outcomes.

Vascular smooth muscle cells (VSMCs) exhibit a remarkable phenotypic spectrum in response to injury, inflammation, metabolic stress, and aging through state changes encoded in chromatin. This review examines how DNA methylation and hydroxymethylation, histone modifiers, chromatin readers, adenosine triphosphate (ATP)-dependent chromatin remodelers, three-dimensional genome organization, and non-coding RNAs (ncRNAs) shape VSMC plasticity in intimal hyperplasia, atherosclerosis and vascular aging. Bromodomain-containing protein 4 (BRD4) is used as a case study because it links acetyl-lysine recognition to transcriptional programs and BRD4 inhibition has been reported to affect VSMC biology in vivo. Based on published evidence, we discuss the timing and delivery of potential vascular epigenetic targeting: short-term, local chromatin-directed therapy may help restrain maladaptive VSMC proliferation after acute artery injury, whereas chronic conditions, including atherosclerosis and vascular aging, would require careful long-term dosing that preserves endothelial repair, VSMC contractile state and hematopoietic safety. These therapeutic implications remain preclinical hypotheses, with clinical efficacy remaining to be established.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease lacking effective pharmacological therapies. To identify potential therapeutic targets and candidate compounds, we performed integrative genetic analyses for drug repurposing by combining Mendelian randomization (MR), summary-data-based Mendelian randomization (SMR), and Bayesian colocalization. This framework prioritized multiple druggable candidates, among which STAT3 emerged as a key regulatory node. Subsequent functional studies demonstrated that emodin suppressed vascular smooth muscle cell proliferation, migration, phenotypic switching, and inflammatory responses. These effects were accompanied by reduced STAT3 phosphorylation and nuclear localization. Molecular docking suggested a potential binding mode of emodin within the STAT3 SH2 domain, while cellular thermal shift assays demonstrated thermal stabilization of STAT3 by emodin in intact cells, consistent with target engagement. Notably, emodin and the selective STAT3 inhibitor STAT3-IN-13 produced comparable effects, and co-treatment did not yield additive efficacy, suggesting overlapping mechanisms. In vivo, emodin attenuated aneurysm development and reduced vascular inflammation in experimental models. Collectively, these findings identify emodin as a candidate modulator of AAA progression acting through suppression of STAT3-associated signaling pathways, and demonstrate the potential of genetic evidence-guided drug repurposing strategies in complex vascular diseases.

Smooth muscle cells (SMCs) are essential for the normal function of the cardiovascular, respiratory, gastrointestinal, and urogenital systems, and SMC dysfunction contributes to a wide range of genetic and acquired diseases. CRISPR-based genome editing provides new approaches for studying SMC biology and developing therapies for smooth muscle disorders. In particular, base editing and prime editing enable precise nucleotide changes without introducing DNA double-strand breaks. In this review, we summarize recent applications of CRISPR technologies in smooth muscle biology, with a primary focus on vascular diseases. We discuss how CRISPR-engineered primary cells, induced pluripotent stem cell-derived SMCs (iPSC-SMCs), and animal models have been used to investigate disease mechanisms and validate pathogenic variants. We further review therapeutic genome editing strategies for correcting disease-causing variants in patient-derived iPSC-SMCs, vascular organoids, and preclinical animal models. Finally, we discuss major challenges for clinical translation, including efficient and SMC-specific delivery, immunogenicity, editing precision, off-target effects, and long-term safety. Continued advances in genome-editing technologies, delivery platforms, and human disease models may expand the application of these approaches to smooth muscle disorders.

Altered portal venous hemodynamics are associated with the development of portosystemic collateralization and structural remodeling of the extrahepatic portal vasculature; however, the underlying cellular and molecular mechanisms remain incompletely understood. Existing partial portal vein ligation models rely on fixed-diameter spacers or needle-based ligation to achieve predefined, non-adjustable levels of portal venous flow restriction, thereby producing discrete levels of hepatic inflow. Consequently, they provide limited control over portal blood flow, intrahepatic perfusion, and the extent of extrahepatic portal vein (EPV) remodeling. Here, we developed a custom adjustable EPV ligation system in mice using a precision threaded bolt and double-nut mechanism calibrated with feeler gauges, enabling controlled and quantifiable EPV diameter reduction and systematic investigation of flow-dependent EPV remodeling. Incremental EPV ligation, ranging from 20% to 80% partial ligation as well as complete ligation, produced graded reductions in portal venous flow and hepatic perfusion as measured by laser Doppler flowmetry. In this study, 50% ligation was selected for cellular and histological analyses because it induced robust and reproducible EPV remodeling characterized by luminal narrowing and coordinated intimal and medial hypertrophy. Vascular remodeling was accompanied by splenomegaly, reduced liver mass, and elevated serum transaminases, consistent with alterations in portal venous system hemodynamics and hepatic consequences associated with reduced portal inflow. Time-course analysis demonstrated progressive intimal thickening from 1 to 3 to 5 weeks after ligation, whereas medial thickening plateaued after 3 weeks, revealing compartment-specific temporal kinetics of vascular remodeling. Quantitative nuclear morphometry demonstrated persistent reductions in nuclear area and perimeter, indicating cellular reprogramming in the ligated EPV. In conclusion, this study establishes a versatile EPV ligation platform enabling graded control of portal venous flow reduction and remodeling severity. This model reveals structured, time-dependent EPV adaptation and identifies extrahepatic vascular and nuclear remodeling as flow-driven features of altered portal venous hemodynamics.

Hypertensive cardiac remodeling (HCR) encompasses maladaptive structural and functional changes-including cardiomyocyte hypertrophy, myocardial fibrosis, and ventricular dysfunction-that develop in response to chronic pressure overload. Increasing evidence indicates that inflammation is not merely a secondary consequence of hypertensive stress, but a central driver of cardiomyocyte injury, myocardial fibrosis, and ventricular remodeling. Among the inflammatory mechanisms involved, the NLRP3 inflammasome and neutrophil extracellular trap formation, or NETosis, have emerged as interconnected amplifiers of sterile inflammation and hypertensive cardiac remodeling. NLRP3 inflammasome activation promotes caspase-1-dependent maturation of IL-1β and IL-18, pyroptotic cell death, and profibrotic signaling, whereas excessive NETosis releases extracellular DNA, histones, and myeloperoxidase, thereby exacerbating oxidative stress, immune activation, and myocardial injury. These two pathways may form a self-amplifying inflammatory circuit in which inflammasome-derived cytokines promote NETosis, while NET-associated components further activate NLRP3 signaling. In this review, we summarize current evidence on NLRP3 inflammasome-NETosis crosstalk in hypertensive cardiac remodeling, with emphasis on cellular mediators, pathological relevance, and therapeutic intervention points. We also discuss potential strategies targeting this crosstalk, including inflammasome inhibition, suppression of NET formation, NET clearance, and indirect immunometabolic modulation. Finally, we address major translational challenges, including target specificity, therapeutic timing, host-defense impairment, and limited clinical evidence. Understanding NLRP3 inflammasome-NETosis crosstalk may provide new opportunities for inflammation-driven hypertensive cardiac remodeling.

Aquaporins (AQPs) are transmembrane proteins that primarily transport water, but certain isoforms also facilitate the diffusion of small neutral signaling molecules, such as hydrogen peroxide (H2O2) and nitric oxide (NO). However, whether AQPs mediate vascular H2O2 and NO transport remains poorly understood. We investigated whether AQPs facilitate the transport of these endothelium-derived relaxing factors using relaxation assays in isolated male Wistar rat aortas. Incubation with diphenyleneiodonium (non-specific NADPH oxidase inhibitor), VAS2870 (pan-NADPH oxidase inhibitor), diethyldithiocarbamate (superoxide dismutase inhibitor), exogenous peroxidase, AgNO3 (non-selective AQP inhibitor), or bacopaside II (selective AQP1 inhibitor) significantly attenuated carbachol-stimulated endothelium-dependent relaxation. Vasorelaxation induced by exogenous H2O2 was reduced by AgNO3 or bacopaside II; however, in endothelium-denuded rings, AgNO3 - but not bacopaside II- attenuated this response. Furthermore, both AgNO3 and bacopaside II decreased relaxation mediated by the intracellular NO donor sodium nitroprusside. Concomitantly, in endothelium-denuded segments, vasorelaxation induced by the extracellular NO donor spermine NONOate was diminished by AgNO3, but was slightly increased by bacopaside II. Collectively, these findings suggest that during endothelium-dependent vasorelaxation, AQP1 facilitates endothelial H2O2 influx and subsequent NO efflux, rather than promoting their entry into vascular smooth muscle cells. Thus, our work uncovers a coordinated H2O2-NO signaling cascade that drives endothelium-dependent relaxation in the rat aorta via AQP1-mediated transport, providing novel insights into the biophysical mechanisms governing endothelial function.

Lymphedema is a chronic disease characterized by impaired lymph drainage and accumulation of protein-rich interstitial fluid, which progresses to develop irreversible fibrosis. Despite its substantial clinical burden, effective pharmacological therapies that improve lymphatic function and prevent disease progression remain lacking. Given the prominent inflammatory and fibrotic responses associated with lymphedema, we investigated the therapeutic potential of IVA337 (lanifibranor), a pan-peroxisome proliferator-activated receptor (PPAR) agonist that activates PPARα, PPARβ/δ, and PPARγ, key regulators of lipid metabolism, inflammation, and fibrosis. Here, we evaluated the therapeutic efficacy of IVA337 during the early stage of surgery-induced secondary lymphedema in mice and investigated the underlying mechanisms. IVA337 administration alleviates lymphedema progression, improves lymphatic drainage, reduces dermal thickness, and resolves lymphatic vessel dilation. Mechanistically, IVA337 suppresses TGFβ/SMAD2/3 signaling pathway, reduces immune cells infiltration, and improves lymphatic vessels integrity. In human dermal lymphatic endothelial cell (HDLEC), IVA337 attenuates TGFβ induced SMAD2/3 phosphorylation and preserves the expression of cell junction Claudin5, reduces VE-Cadherin-stained cell-cell gaps. Collectively, our findings demonstrate that IVA337 protects against early-stage lymphedema by suppressing TGFβ/SMAD2/3 signaling and limiting inflammatory and fibrotic and lymphatic endothelial dysfunction. These findings identify pan-PPAR activation as a promising pharmacological strategy to preserve lymphatic function during the early phase of lymphedema and potentially prevent progressive tissue fibrosis.