Shinsuke Kikuchi

Peripheral artery disease (PAD) is most commonly caused by atherosclerotic arterial stenosis or occlusion, which reduces downstream tissue perfusion and causes tissue ischemia. In response to ischemia, reparative angiogenesis is activated and may support tissue perfusion recovery and skeletal muscle protection. In contrast, neovascularization within atherosclerotic plaques may promote intraplaque hemorrhage and plaque destabilization. Thus, angiogenesis has dual roles in PAD-related ischemia and atherosclerotic plaques. Extracellular vesicles (EVs) are membrane-bound particles that carry various cargo, including proteins, lipids, nucleic acids, and metabolites. Through the transfer of bioactive cargo and surface-mediated signaling, EVs can modify recipient-cell functions and thereby influence angiogenic signaling. Investigation of EV-mediated communication may therefore help elucidate the mechanisms underlying angiogenic regulation in vascular disease. In addition, disease-promoting EVs may be therapeutically targeted, whereas engineered EVs may be developed as therapeutic agents or delivery platforms. Recent studies have shown that EVs regulate angiogenic responses in preclinical murine hindlimb ischemia models. However, these effects in ischemic limbs and the potential involvement of EVs in atherosclerotic plaque neovascularization have rarely been reviewed in an integrated manner. This narrative review discusses these contrasting angiogenic processes from a context-dependent perspective. Understanding this context dependency may help develop EV-based strategies that promote functional vascular repair in ischemic tissues while suppressing or normalizing pathological neovascularization in atherosclerotic plaques.

Yuki Tada, Shinsuke Kikuchi, Sayaka Yuzawa, Mishie Tanino, Ryo Mitsutake, and Nobuyoshi Azuma. Vasc Specialist Int 2026;42:. https://doi.org/10.5758/vsi.260095

Dedicated venous stents became available in Japan only recently, and reports of their use and follow-up in Japanese practice remain scarce. A 77-year-old woman developed acute left iliofemoral deep vein thrombosis (DVT) after prolonged recumbency and was treated with edoxaban. Eighteen days later she underwent endovascular therapy of the right lower limb for chronic limb-threatening ischaemia, and aspirin was added. Limb swelling and pain persisted despite three months of anticoagulation and graduated compression, and imaging then showed chronic occlusion of the left common and external iliac veins (EIV) with patent femoral and deep femoral inflow, corresponding to a favourable anatomical category of chronic venous obstruction (CVO). Under intravascular ultrasound (IVUS) guidance, which identified a stenotic distal landing zone in the proximal common femoral vein (CFV) that was not evident on venography, two Venovo venous stents (Becton, Dickinson and Company (BD), Tempe, AZ, USA) were deployed from the common iliac vein (CIV) to the CFV. Symptoms and clinical severity scores improved over the following months. Three months after stenting, duplex surveillance detected a localised mural thrombus along the posterior wall of the stent despite treatment with edoxaban and aspirin; the antiplatelet agent was changed to clopidogrel, yet the thrombus enlarged from 3 to 6 mm over the next six months before reaching a plateau. Nine months after stenting, an occult breast carcinoma was diagnosed incidentally. The stent remained patent at 12 months, through two bleeding events and three interruptions of antithrombotic therapy. This case illustrates one approach to managing an asymptomatic in-stent mural thrombus and raises the possibility that a thrombus forming despite adequate antithrombotic therapy may be an early manifestation of an undiagnosed malignancy.

Background: Vein graft failure due to intimal hyperplasia and maladaptive remodeling remains a major limitation of peripheral bypass surgery. Although vascular remodeling is recognized as a multilayered process, layer-specific molecular mechanisms that distinguish adaptive from negative remodeling remain incompletely understood. We aimed to investigate the vascular microenvironment of patent and stenotic grafts using spatial transcriptomics. Methods: Vein specimens were obtained from three patients undergoing revision surgery. For each patient, a matched set of three samples was collected: unused saphenous vein (Denovo), normally healed vein graft (Non-stenosed), and stenosed vein graft (Stenosed) (n = 3 patients). GeoMx Digital Spatial Profiling with the Human Whole Transcriptome Atlas was used to map gene expression across intima, medial, and adventitial layers. Differential expression, gene ontology, spatial deconvolution, and immunohistochemistry were integrated for analysis. Results: Non-stenosed and Stenosed grafts shared transcriptional features distinct from Denovo veins, particularly in pathways related to cell proliferation. Non-stenosed grafts showed increased expression of CDKN1A across all vascular layers, whereas Stenosed grafts exhibited enhanced mitogen-activated protein kinase (MAPK) pathway activity, reduced DUSP1 -mediated regulation, and increased macrophage accumulation. ECM remodeling showed layer-specific organization, with VCAN and ACAN enriched in the intima and DCN in the adventitia, while Stenosed grafts demonstrated a trend toward collagen-dominant remodeling. Cell deconvolution suggested a shift toward vascular smooth muscle cell (VSMC)-dominant architecture after arterialization, with modest enrichment of synthetic VSMC signatures in stenotic regions. Conclusions: Vein graft stenosis appears to be associated with layer-specific alterations in cell cycle regulation, inflammatory signaling, extracellular matrix remodeling, and VSMC phenotype. Spatial transcriptomic analysis reveals molecular heterogeneity not captured by bulk approaches and provides preliminary insight into graft remodeling. These findings may inform future studies to improve long-term graft patency.