Attenuation of medial arterial calcification by senescent vascular smooth muscle cell clearance: a uPAR-targeted senolytic therapy
M Zhang, C H Xie, H Yu, D Wang, Q He, Y Kong, Z H Zhang, H HuangAbstract
Background
Medial arterial calcification is a severe vascular pathology and independent predictor of adverse cardiovascular events and mortality. Affecting over half of the older adult population, it reduces 10-year survival by more than 10%. Ageing accelerates this process by inducing a senescent phenotype in vascular smooth muscle cells. Despite this profound clinical impact, no disease-modifying therapies exist. Whether selectively clearing senescent vascular smooth muscle cells can inhibit calcification, and how to mitigate the off-target effects of conventional senolytics, remain critical unanswered questions. This highlights an urgent unmet clinical need.
Purpose
This study aimed to develop a uPAR-targeted senolytic strategy to safely eliminate senescent vascular smooth muscle cells as a potential therapy for medial arterial calcification.
Methods
We analysed clinical data from patients at our centre and from mouse models to assess the relationship of age and dasatinib treatment with medial arterial calcification and urokinase-type plasminogen activator receptor (uPAR) expression. We designed a uPAR-targeting peptide (U10) and formulated uPAR-targeted nanoparticles loaded with dasatinib and quercetin (D&Q) (U10-D&Q-LPs). Therapeutic effects were evaluated in two mouse models of medial arterial calcification using SA-β-gal staining, alizarin red staining, and immunohistochemistry.
Results
Dasatinib treatment reduced medial arterial calcification in patients. Furthermore, the senolytic combination of D&Q proved superior to dasatinib alone, more effectively eliminating senescent vascular smooth muscle cells and suppressing medial arterial calcification. We identified uPAR as a highly upregulated surface marker on senescent and calcified vascular smooth muscle cells. Given the species specificity of uPAR, we developed U10 as a targeting peptide specific to mouse uPAR. U10-D&Q-LPs exhibited enhanced uptake by these cells. In two mouse models of medial arterial calcification, systemic administration of U10-D&Q-LPs significantly reduced calcification while eliminating off-target toxicities associated with free dasatinib, including thrombocytopenia and neutropenia. Notably, U10-D&Q-LP treatment improved survival, ameliorated multiorgan damage—myocardial calcification, bone marrow adiposity, and splenic white pulp atrophy—and improved overall health status (body weight, activity).
Conclusion
This study establishes a novel, highly effective, and safe therapeutic strategy for medial arterial calcification through uPAR-targeted elimination of senescent vascular smooth muscle cells. Given the established role of cellular senescence in cardiovascular pathology, these findings may inform the development of senolytic interventions for a broader range of age-related cardiovascular diseases.Abstract pictureFor image description, please refer to the figure legend and surrounding text.Result figureFor image description, please refer to the figure legend and surrounding text.