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Thrombospondin-4 regulates apoptosis of vascular smooth muscle cells after artery transplanted into vein

ABSTRACT: In the context of coronary artery bypass grafting (CABG), mechanical factors are pivotal; however, the molecular underpinnings of vascular atrophy and remodeling subsequent to arterial transplantation into a venous hemodynamic milieu remain enigmatic. Consequently, this study employed the vascular anastomosis wheel technique to graft the common carotid artery of New Zealand white rabbits into the external jugular vein, thereby establishing an innovative animal model of arterial mechanical unloading. The efficacy of the animal model was ascertained through ultrasound imaging. Immunohistochemical methodologies, transmission electron microscopy, and TUNEL staining were utilized to delineate alterations in vascular morphology. Advanced techniques such as gene transcriptomic analysis, proteomic profiling, iPathway guide (IPG) analysis, gene overexpression/silenced, flow cytometry, and stretch testing were applied to elucidate the potential molecular mechanisms. Comparative analysis between the arterial graft and the control group revealed the successful preparation of the mechanical unloading animal model in vitro. Morphological examination of the arterial vessels indicated that atrophy under venous flow mechanics is predominantly attributed to the apoptosis of vascular smooth muscle cells (VSMCs). Genomic and proteomic analyses revealed that thrombospondin-4 (THBS4) plays a pivotal role in vascular remodeling. IPG analysis suggested that THBS4 may modulate VSMCs apoptosis via the focal adhesion pathway. THBS4 gene overexpression/silence experiments and flow cytometry demonstrated the regulation of VSMCs apoptosis by THBS4. Furthermore, it was established that low stretch tension facilitates the expression of THBS4 and VSMCs apoptosis, thereby confirming the relationship between THBS4 and VSMCs apoptosis. This study was the first to introduce gene transcriptomics and proteomics into the arterial mechanical unloading animal model and the first to demonstrate the role of THBS4 in promoting VSMCs apoptosis. Consequently, THBS4 emerges as a promising therapeutic target for the prevention of intimal hyperplasia post-vascular transplantation in vascular surgery.

ORGANISM(S): Oryctolagus cuniculus

PROVIDER: GSE289973 | GEO | 2026/01/12

REPOSITORIES: GEO

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Project description:Aging is an independent risk factor for cardiovascular disease. Preventing age-induced arterial dysfunction and the associated risk of cardiovascular disease remains a signiﬁcant clinical challenge. Aerobic exercise, which induces a temporary increase in both blood flow and pressure in active tissue, has been shown to reduce macroscale arterial stiffening in humans. The purpose of this study was to investigate the effects of mechanical stimuli on improving aging pathophysiology of VSM cells isolated from soleus feed arteries (SFA). We hypothesized that exposure to external mechanical stimulation enhances formation of smooth muscle alpha-actin (SMα-actin) fibers and cell-matrix adhesions in aged VSM cells. Ex-vivo functional studies were used to assess myogenic contractility of VSM in isolated SFA from young (4 months) and old (24 months) Fischer 344 rats. These data indicated that pre-treatment of isolated aged SFA with a short-duration increase in intraluminal pressure rescued contractility. The mechanical stretch-induced remodeling of the cellular architecture was assessed in VSM cells isolated from young and old SFA. To dissect the mechanisms involved, the structural and functional properties of VSM cells were assessed by using mechanical stimulation combined with fluorescence confocal microscopy. Results showed that aged VSM cells respond faster than young cells to 2D biaxial cyclic stretch by increasing actin stress fiber formation and vinculin recruitment at cell-matrix adhesions. In addition, hydrostatic pressure treatment applied to aged VSM cells plated on stiffer substrates restores actin fibers and integrin β1 recruitment. Taken together, these findings suggest that discrete VSM cell mechanical properties and their ability to adapt to external mechanical signals are key in restoring VSM contractility in aging. These results are significant because they provide a novel understanding of the mechanisms by which mechanical stimulation improves VSM contractility in aged resistance arteries. Our results provide new insights into the role of VSM in vascular aging and highlight a new direction for mitigating age-related effects via mechanical stimulation-induced VSM remodeling.

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Thrombospondin-4 regulates apoptosis of vascular smooth muscle cells after artery transplanted into vein

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