Cerebrovascular diseases are the leading cause of death and long-term disability worldwide, including ischemic stroke, intracerebral hemorrhage, intracranial aneurysms, and cerebrovascular malformations, imposing a heavy burden on society and families. Organoid technology, as a major breakthrough in the field of biomedicine, provides a new platform for the study of cerebrovascular diseases. By constructing organoid-based models of cerebrovascular diseases, researchers can simulate their pathogenesis in vitro and deeply explore key links such as angiogenesis and neurovascular unit interactions, providing a new platform for the early diagnosis of the diseases, the discovery of treatment targets, and drug development. This review summarizes the current progress of organoid technology in cerebrovascular disease research, focusing on model establishment and mechanistic investigations of disorders such as cerebral cavernous malformations, ischemic stroke, and hemorrhagic stroke. Furthermore, we discuss the potential applications and current limitations of organoid platforms in disease modeling, drug screening, and future translational research. Although organoid technology holds promise for advancing precision medicine, further optimization, validation, and integration with clinical studies are required before broader clinical applications can be realized.

Heart failure with preserved ejection fraction (HFpEF) is increasingly linked to coronary microvascular dysfunction (CMD), but early, mechanism-resolved phenotyping remains challenging. We developed a multimodal, non-invasive imaging platform to interrogate CMD in a double-hit HFpEF mouse model induced by high-fat diet and chronic nitric oxide synthase inhibition (L-NAME). C57BL/6 mice underwent cine and strain cardiac MRI, dynamic contrast-enhanced MRI with macromolecular (galbumin) and redox-sensitive (3CP) contrast agents, and Doppler-based assessment of coronary flow reserve induced by multiple vasodilators. Ex vivo coronary micro-CT angiography, transmission electron microscopy, coronary endothelial cell transcriptomics, and high-energy phosphate and NAD(H) profiling in heart and blood were performed. Double-hit mice developed an early HFpEF-like phenotype with hypertension, metabolic dysfunction, exercise intolerance, lung congestion, increased natriuretic peptides, impaired diastolic relaxation, longitudinal strain and dobutamine reserve, with preserved systolic function. Coronary tree size and length were maintained, but branching complexity was reduced and ultrastructure revealed endothelial swelling, mitochondrial damage and perivascular/interstitial remodeling. Galbumin DCE-MRI demonstrated increased Ktrans, consistent with microvascular barrier failure, whereas 3CP imaging suggested enhanced myocardial reduction capacity. Coronary flow reserve was globally blunted across endothelium-dependent and -independent vasodilators, with elevated basal coronary flow. Endothelial and cardiac transcriptomics indicated inflammatory, fibrotic and redox-stress signatures, while bioenergetic analysis showed ATP and NAD+ depletion with diminished myocardial creatine buffering. This platform sensitively captured early, predominantly functional CMD without overt rarefaction in double-hit HFpEF mice. These results identify impaired vasodilatory reserve, increased endothelial permeability, vascular inflammatory and fibrotic activation, and capillary extracellular matrix deposition as early pathophysiological events.

High-glucose (HG) stress induces dysfunction of vascular endothelium, a key factor contributing to diabetic vascular complications, in part through ferroptosis. However, the mechanisms governing ferroptosis under these conditions remain partially understood. Herein, we identified circFBXO7 as a novel circular RNA that promotes ferroptosis and endothelial injury in human umbilical vein endothelial cells (HUVECs) and immortalized human aortic endothelial cells (iHAECs) treated with HG. Transcriptomic profiling revealed that circFBXO7 was markedly upregulated upon HG exposure and positively correlated with ferroptosis-related genes. Functional experiments showed that silencing circFBXO7 alleviated HG-induced cell death, restored migration and tube formation, and reduced oxidative stress, lipid peroxidation, Fe[2+] accumulation, and mitochondrial damage. Mechanistically, circFBXO7 interacted with the transcription factor cellular promoter 2 (TFCP2) and promoted its ubiquitination and proteasomal degradation. Rescue experiments demonstrated that TFCP2 inhibition abolished the protective effects of circFBXO7 knockdown and sensitized endothelial cells to HG-induced ferroptosis. Overexpression of TFCP2 inhibited ferroptosis caused by HG treatment. Collectively, these findings identify a novel circFBXO7-TFCP2 regulatory axis linking metabolic stress to endothelial ferroptosis, providing new insight into the molecular basis of diabetic vascular dysfunction.

Diabetic Cardiac Autonomic Neuropathy (DCAN) is a prevalent and severe yet underdiagnosed complication of diabetes characterized by progressive injury to autonomic nerve fibers that regulate cardiovascular functions. This multifactorial disorder contributes significantly to morbidity and mortality due to arrhythmias, silent myocardial ischemia, and sudden cardiac death. DCAN onset is often insidious, with early stages marked by subclinical autonomic dysfunction detectable through heart rate variability and reflex testing. The pathogenesis involves chronic hyperglycemia-induced oxidative stress, mitochondrial dysfunction, and microvascular damage, compounded by genetic predispositions and complex epigenetic and epitranscriptomic modifications affecting gene expression in autonomic nerves. Notably, non-coding RNAs such as long non-coding RNAs (lncRNAs) play critical roles in diabetic neuropathy (DN) pathophysiology by modulating inflammatory and neurodegenerative pathways. Current management remains focused on stringent glycemic control, comprehensive cardiovascular risk reduction, lifestyle modifications, and symptom-targeted pharmacotherapies. Despite these measures, effective disease-modifying treatments are limited, underscoring the need for novel therapeutic approaches. This review synthesizes DCAN's molecular pathology, and genetic advances, highlighting innovative CRISPR and gene therapy strategies poised to revolutionize its diagnosis and treatment.

Abdominal aortic aneurysm (AAA) is driven by chronic inflammation and extracellular matrix (ECM) degradation. Elastase-2 (Ela-2) is a conserved chymotrypsin-like serine protease encoded by the human gene CELA2A and its murine ortholog Cela2a, and it generates angiotensin II and contributes to cardiovascular remodeling. However, its role in AAA remains undefined. This study characterizes Ela-2 in human (AAA n = 41; controls n = 21) and experimental AAA. Ang II-infused wild-type (Wt) and Cela2a Knockout (Cela2a-/-, Cela2a KO) mice were analyzed for Ela-2 expression, cytokines, and ECM markers. Human AAA showed marked Ela-2 upregulation, elevated IL-6/IL-8/CCL5, macrophage infiltration, and increased Osteopontin N-terminal fragment (OPN-N) alongside MMP-2/9 activity. WT + Ang II mice recapitulated this phenotype with aortic dilation, inflammation, ECM disruption, and OPN-N accumulation, whereas Cela2aKO mice +Ang II were protected. Structural modeling confirmed active site conservation enabling angiotensin cleavage and ECM proteolysis. Ela-2, encoded by the human gene CELA2A, emerges as a key proteolytic driver of AAA progression and a promising therapeutic target.

Human vascular function depends on tightly coordinated structural, mechanical, and cellular interactions, yet these features remain difficult to recapitulate in vitro. Induced pluripotent stem cells (iPSCs) enable efficient generation of vascular cell types, including endothelial cells, smooth muscle cells, and pericytes, but current systems often lack functional maturity and physiological relevance. Recent advances in vascular organoid engineering provide new opportunities to address this limitation. By integrating self-organization, co-culture, and bioengineering approaches, iPSC-derived systems can form three-dimensional vascular networks with increasing physiological relevance. Emerging evidence from studies of iPSC-derived vascular systems, spanning both two-dimensional differentiation models and three-dimensional organoid platforms, highlights the critical roles of hemodynamic cues, including shear stress and perfusion, together with metabolic and immune signaling, in driving the coordinated maturation of endothelial and mural compartments. These platforms enable modeling of key vascular pathologies, including inflammation, vascular remodeling, and barrier dysfunction, while gene editing further facilitates mechanistic investigation in patient-specific contexts. Together, iPSC-derived vascular systems provide a scalable and physiologically relevant platform for disease modeling, drug discovery, and regenerative medicine.

Coronary artery disease presents as an obstruction to coronary blood flow due to the presence of a vascular lesion. Treatment options include percutaneous transluminal coronary angioplasty and the deployment of a vascular stent to keep the artery open. However, in-stent restenosis can still occur because of neointimal hyperplasia driven by the accumulation of vascular smooth muscle cell (VSMC)-like cells within the stented vessel segment. Drug-eluting stents (DES) reduce restenosis by locally releasing anti-proliferative agents. Yet, current DES platforms are limited by fixed drug loading at implantation and the inability to replenish the drug at the stent after depletion. Here, we developed a magnetically responsive nanoparticle platform as a proof-of-concept strategy for targeted stent drug reloading. Poly (lactic-co-glycolic acid) magnetite nanoparticles (PLGA-MNPs) were engineered to encapsulate paclitaxel or the γ-secretase inhibitors, DAPT and Compound E. Nanoparticles were characterised by dynamic light scattering, electron microscopy, and inductively coupled plasma atomic emission spectroscopy. Their ability to bind stainless steel stents, release drugs, and modulate cellular responses was examined in vitro. PLGA-MNPs exhibited a mean hydrodynamic diameter of ∼215 nm with low polydispersity and stable suspension properties. Fluorescence imaging demonstrated increased retention of FITC-labelled PLGA-MNPs on stainless steel stents in the presence of a static magnetic field. Paclitaxel-loaded PLGA-MNPs inhibited murine mesenchymal stem cell proliferation, with enhanced efficacy observed under magnetic field exposure. Similarly, γ-secretase inhibitor-loaded PLGA-MNPs attenuated Jagged-1-induced expression of myogenic and Notch-responsive genes in vitro. Drug release from PLGA-MNPs was increased in the presence of a magnetic field over extended incubation periods. Notably, exposure to a static magnetic field alone also influenced gene expression, indicating that magnetic field effects must be considered when interpreting biological outcomes. Collectively, these findings demonstrate the feasibility of magnetically responsive PLGA-MNPs as a stent-targeted drug delivery platform. Further studies under physiological flow conditions and in vivo vascular injury models will be required to establish safety, targeting efficiency, and therapeutic efficacy.

Cardiac involvement in rheumatoid arthritis (RA) is an uncommon but clinically relevant manifestation that may extend beyond pericardial and valvular disease to involve peri-annular and subvalvular fibrous structures. Aneurysmal and pseudoaneurysmal complications affecting the left ventricular outflow tract (LVOT), aortic root, and adjacent regions are exceptionally rare and largely described in isolated case reports. We performed a systematic review of the reported cases to characterize the clinical, imaging, pathological, and therapeutic features of RA-associated aneurysmal or pseudoaneurysmal cardiac involvement. The review identified a small number of reported cases in which RA-related inflammation involved peri-annular structures, often mimicking infective endocarditis and frequently associated with significant valvular dysfunction. Across cases, multilevel structural involvement, including the aortic root, LVOT, membranous interventricular septum, and cardiac valves, was common. High-grade atrioventricular conduction disturbances were observed in a substantial proportion of patients, reflecting the close anatomical relationship between inflammatory lesions and the cardiac conduction system. Multimodality imaging, combining transthoracic and transesophageal echocardiography with cardiac computed tomography, cardiac magnetic resonance, or FDG-PET/CT, was consistently required to define anatomical extent and guide management. Histopathological examination, when available, proved essential to exclude infection and demonstrated granulomatous inflammation or rheumatoid nodules in autoimmune-mediated cases. Most patients required surgical intervention due to advanced structural disease, while isolated inflammatory involvement without aneurysmal degeneration responded to immunosuppressive therapy. Outcomes were generally favorable. This review underscores that RA-related cardiac inflammation may predispose to aneurysmal degeneration of peri-annular fibrous structures, with complex presentations in which a complete diagnostic pathway, including multimodality imaging and pathological confirmation is critical.

Aortic aneurysm is a fatal vascular disease lacking effective drug therapies. Its pathogenesis is complex, with traditional studies mainly focusing on endothelial cells in the intima and smooth muscle cells in the media. Recent studies have shown that aortic adventitia is a key driver of pathological progression, with an increasingly prominent role in the disease process. The core scientific question centers on how diverse adventitial cell populations are activated and how their interactions collectively drive the vicious cycle of chronic inflammation, extracellular matrix degradation, and pathological remodeling. This review summarizes the multifaceted roles of the adventitia in aortic aneurysm development, focusing on interactions among adventitial cell types (fibroblasts, immune cells and progenitor cells), the vasa vasorum, perivascular adipose tissue, and local immune responses, and highlights potential strategies for targeting the adventitial microenvironment.

Caveolin-1 (CAV1), the principal structural protein of caveolae, is a critical regulator of endothelial homeostasis, vascular aging, and frailty in older adults. By scaffolding multiple signaling pathways and controlling endothelial nitric oxide synthase activity, CAV1 shapes nitric oxide bioavailability, oxidative stress responses, and vascular stiffness. In parallel, extracellular vesicles (EVs) derived from endothelial cells, platelets, and other vascular cells act as key mediators of intercellular communication, propagating senescence, inflammation, and thrombosis across the vascular tree. This narrative review synthesizes current evidence on the CAV1-EV axis as a mechanistic nexus linking endothelial dysfunction, cardiovascular disease, and geriatric syndromes, with a particular focus on frailty. We first summarize the structure, regulation, and post-translational modifications of CAV1, especially tyrosine-14 (Tyr-14) phosphorylation, and their impact on endothelial senescence and dysfunction. We then examine how CAV1 controls EV biogenesis, cargo loading, and uptake, and how CAV1-enriched EVs contribute to pro-inflammatory and prothrombotic phenotypes in aging and frail populations. Finally, we discuss the translational potential of CAV1-related EVs as circulating biomarkers for early vascular aging and as targets for geroscience-guided interventions, including engineered or mesenchymal stem cell-derived EVs with vasculoprotective cargo. By integrating molecular, vascular, and geriatric perspectives, this review proposes the CAV1-EV axis as a promising framework for risk stratification and vascular-targeted therapies aimed at preserving function and independence in older adults.

Fibrin clot architecture is increasingly recognized as a determinant of thrombotic phenotype and a potentially modifiable endpoint in vascular pharmacology. Aspirin is established as an antiplatelet agent through irreversible cyclooxygenase-1 acetylation and thromboxane A2 suppression. Beyond this canonical pathway, aspirin has been proposed to modulate fibrin clot properties through nonenzymatic Nε-lysine acetylation of fibrinogen. Experimental studies in purified, recombinant, and selected ex vivo systems suggest effects on fibrin polymerization, factor XIIIa-dependent cross-linking, clot permeability, viscoelasticity, and fibrinolysis, with aspirin-sensitive lysines identified across fibrinogen chains. However, clinical relevance remains uncertain. At clinically relevant exposure, fibrinogen acetylation appears generally low, and contemporary low-dose aspirin does not consistently increase acetylation or modify clot phenotype despite effective platelet thromboxane suppression. Disease-related modifications, including glycation, carbamylation, oxidation, and nitration, may further reshape fibrin structure and influence aspirin responsiveness. This review examines the biochemical rationale, experimental evidence, disease-context dependency, and limitations of aspirin-mediated fibrinogen acetylation as a proposed extra-platelet mechanism. Its biological significance will require quantitative evidence of site occupancy, residue-specific function, physiological aspirin exposure, standardized clot assays, and integration with disease-specific modifiers of fibrin phenotype.