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.
BACKGROUND:Free fatty acid receptor 4 (FFAR4) activation modulates adipogenesis, but this pathway has not been explored in the context of perivascular adipose tissue (PVAT) dysfunction and vascular remodeling. METHODS:Adipose tissue-specific FFAR4 knockout (Adipo-Ffar4-/-, Adipo-KO) mice were generated by crossing Adipoq-Cre and Ffar4flox/flox (WT) mice. FeCl₃-induced PVAT injury model in abdominal aorta was established. TUG-891 (20 mg/kg/day, i.p.) was administered for 4 weeks. In vitro, FeCl₃-conditioned medium was prepared with mouse PVAT explants. Proliferation and migration of vascular smooth muscle cells (VSMCs) cultured with conditioned medium were assessed. RESULTS:FFAR4 was particularly upregulated in abdominal aortic PVAT in response to high-fat diet feeding. TUG-891-mediated FFAR4 activation in PVAT alleviated abdominal aortic dysfunction and hyperplasia in WT mice. TUG-891 also prohibited aberrant lipolysis and browning, as evidenced by lower serum FFA levels and downregulated UCP1 expression, in a FFAR4-dependent manner. Expression of pro-remodeling genes (CCL2, MMP9, SPP1) in damaged PVAT was reduced by TUG-891. These protective effects were absent in Adipo-KO mice. In vitro, conditioned medium from FeCl₃-primed PVAT promoted VSMC proliferation and migration, which was attenuated by TUG-891 in the presence of FFAR4. Free fatty acids also enhanced VSMC proliferation and migration. These effects were abolished when using PVAT or cells from Adipo-KO mice. CONCLUSION:These results indicate that TUG-891 mitigates vascular hyperplasia and remodeling by activating FFAR4 in PVAT, reducing lipolysis and suppressing aberrant adipocyte browning. Targeting PVAT FFAR4 signaling may represent a promising therapeutic strategy for vascular diseases.
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.
BACKGROUND:Pulmonary hypertension (PH) is a life-threatening blood vessel disorder marked by remodeling of the pulmonary arteries. A key feature of this process is the uncontrolled growth of pulmonary artery smooth muscle cells (PASMCs). Although changes in fatty acid metabolism are thought to drive this abnormal cell growth, the exact molecular mechanisms behind it are still not fully understood. OBJECTIVE:This study aimed to identify key regulators of fatty acid metabolism in PH using multi-omics data and lab experiments, and to explore how they contribute to PASMC overgrowth, with the goal of uncovering new treatment targets. METHODS:We analyzed PH-related transcriptome data (GSE113439) and protein interaction networks to pinpoint central fatty acid metabolism genes. Functional enrichment, immune cell infiltration, and single-cell RNA sequencing (GSE210248) were used to explore the role of a key gene, ACSL4. We then screened FDA-approved drugs for potential ACSL4 inhibitors using molecular docking and dynamics simulations. Finally, in a rat model of PH induced by chronic low oxygen and in primary PASMCs, we tested how blocking ACSL4 (with the inhibitor PRGL493 or siRNA) affected cell growth and the pathways involved. RESULTS:ACSL4 stood out as a central player in fatty acid metabolism in PH. Its high expression was linked to changes in the immune environment and early disease stages. Functional analysis showed that ACSL4 and its related networks are involved in lipid metabolism, PPAR signaling, and ferroptosis. Virtual screening and molecular dynamics pointed to three FDA-approved drugs that bind tightly and steadily to ACSL4. In lab and animal studies, ACSL4 levels went up in lung tissue and PASMCs exposed to low oxygen, along with shifts in fatty acid profiles and increased PASMC growth. Blocking or silencing ACSL4 eased this overgrowth by helping restore normal VGLL4/YAP levels and reversing the suppression of the Hippo pathway. CONCLUSION:This study uncovers a novel mechanism by which ACSL4 fuels PASMC growth in PH through reshaping fatty acid metabolism and targeting the VGLL4/YAP signaling axis. Although the role of ACSL4 in pulmonary hypertension has been previously reported, its function via the VGLL4/YAP axis is a novel finding. These findings highlight a key pathway in PH progression and point to ACSL4 as a possible target for new treatments.
BACKGROUND:Apolipoprotein E-deficient (ApoE KO) mice develop severe dyslipidemia, atherosclerosis, vascular dysfunction, and hepatic metabolic abnormalities, closely mimicking human cardiometabolic disease. Formoterol fumarate (FF), a long-acting β₂-adrenergic receptor agonist, has been implicated in metabolic regulation; however, its potential novel effects on atherosclerosis-associated multi-organ dysfunction have not been thoroughly characterized. METHODS:Eight-week-old male ApoE KO mice received FF of two doses (0.1 and 0.3 mg/kg/day) or vehicle for 8 weeks. Body weight, serum lipid profiles, and liver and heart damage biomarkers were measured. En face Oil Red O staining and aortic root histopathology assessed atherosclerotic lesion load. Plaque macrophage infiltration was assessed by CD68 immunofluorescence. Isolated aortic ring testing measured vascular reactivity. Cine MRI studied cardiac structure and function. MRI-derived PDFF and R2* mapping were used to assess hepatic fat content and tissue characteristics, respectively. Levels of lipid and collagen in the liver were evaluated. RESULTS:FF treatment significantly reduced serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol in a dose-dependent manner, accompanied by a marked reduction in atherosclerotic plaque burden and CD68-positive macrophage accumulation within plaques. FF dose-dependently improved vascular reactivity by enhancing endothelium-dependent relaxation without affecting endothelium-independent responses. Cardiac MRI demonstrated the FF improved left ventricular systolic function, characterized by reduced end-diastolic and end-systolic volumes and increased ejection fraction, stroke volume, and cardiac output, without changes in heart rate or left ventricular mass. In addition, FF alleviated hepatic lipid deposition and fibrosis, reduced serum aminotransferase levels, and significantly decreased hepatic lipid accumulation as demonstrated by reduced PDFF and R2* values on MRI. CONCLUSIONS:FF confers broad cardiometabolic protection in ApoE KO mice, characterized by lipid lowering, attenuation of atherosclerosis, improvement of vascular and cardiac function, and amelioration of hepatic metabolic abnormalities and fibrosis. These findings provide new evidence for FF as a potential therapeutic candidate for cardiometabolic disease associated with dyslipidemia.
BACKGROUND:Phenotypic switching of smooth muscle cells is a core event in atherosclerosis, and atherosclerosis is recognized as a smooth muscle cell-driven tumor-like disease. Paeoniflorin (PF), a bioactive monoterpene glycoside isolated from Paeonia lactiflora and Paeonia veitchii, which exerts beneficial effects on both cardiovascular diseases and tumors. However, whether it ameliorates atherosclerosis by mediating the phenotypic switching of VSMC to enhance plaque stability remains unclear. The present study aims to clarify the plaque-stabilizing efficacy of paeoniflorin and unravel its underlying mechanisms. METHODS:In vitro, tunicamycin induced VSMC to establish a phenotypic switching model. In vivo, ApoE-/- mice were fed a high-fat diet to induce atherosclerosis. Aortic tissue pathological changes were measured by Oil Red O staining, H&E staining, Sirius red staining, Masson staining, immunofluorescence, and fluorescence staining. Western blotting was employed for mechanistic studies. RESULTS:Our results indicated that PF significantly reduced GRP78 and vimentin expression in VSMC, while increased calponin expression. PF significantly improved cardiac function in ApoE-/- mice, reduced inflammatory factors, oxidative stress, plaque area and necrotic core regions, while increased plaque collagen content and fibrous cap thickness. Furthermore, PF downregulated the expression of aorta GRP78, CHOP, vimentin, osteopontin, KLF4, and MMP2, while upregulated α-SMA and calponin expression. Concurrently, PF activated the AMPK/PPARδ signaling pathway, inhibited GRP78 and vimentin expression, enhanced calponin expression, and improved atherosclerosis. CONCLUSIONS:This study demonstrated that PF inhibited ER stress-induced VSMC phenotypic switching by activated the AMPK/PPARδ signaling pathway, thus enhanced atherosclerosis plaque stability.
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.
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, Fe2+ 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.
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.
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.
BACKGROUND:Acute myocardial infarction (AMI) triggers a systemic inflammatory response that can lead to remote organ damage, including the brain. While the Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5)-mediated canonical WNT pathway is a known regulator of cell survival in peripheral tissues, its role in the brain post-MI is unknown. METHODS:Myocardial infarction was induced in Wt and Lrp5-/- mice and infarct size and mortality were assessed. Serum from these mice was used to treat neuronal cultures. The specific effects of TNF-α were investigated in LRP5-silenced neurons and microglia, with analyses of apoptotic markers, LDH release and key signaling pathways (WNT/β-catenin and NF-κB). RESULTS:Lrp5-/- mice showed significantly higher mortality and larger infarcts and its serum increased the pro-apoptotic profile in differentiated SHSY5Y neurons. TNF-α exerted prosurvival effects in neurons and microglia through distinct mechanisms. In neurons, TNF-α protection was LRP5- and NF-κB-independent while in microglia, TNF-αinduced survival and Bcl2 upregulation required both LRP5 and NF-κB signaling. The canonical WNT pathway was not involved. CONCLUSIONS:LRP5 deficiency aggravates cardiac injury and is associated with increased neuronal susceptibility to inflammatory signals. In vitro, LRP5 selectively mediates TNF-α-dependent survival in microglia via NF-κB while neuronal responses to TNF-α occur through LRP5-independent pathways. These data reveal cell type-specific roles for LRP5 in the inflammatory response to MI and provide a foundation for further mechanistic investigation.
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.
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.
