Senescent cells grow in number with age, lingering to cause harm via inflammatory secretions. This is a problem in every tissue. Here researchers focus on the endothelial lining of blood vessels, and demonstrate that a strategy to reduce the pace at which endothelial cells enter a senescent state can slow the development of vascular stiffness and atherosclerosis in a mouse model of these cardiovascular issues. There are many different ways in which one might go about making cells more resistant to stress-induced senescence, and here the approach is to improve cell defenses against oxidative molecules.
Terazosin (TZ), a well-known antagonist of the α1-adrenergic receptor (α1-AR), has demonstrated protective effects on vascular endothelial cells (ECs) and reduced vascular stiffness in clinical studies. Endothelial dysfunction and oxidative stress are central drivers of cardiometabolic diseases such as diabetes, where sustained reactive oxygen species burden accelerates EC senescence and barrier failure. These findings suggest its potential role in combating vascular aging and atherosclerosis; however, the underlying mechanisms remain partially understood.
In this study, we investigated whether TZ can prevent atherosclerosis in ApoE-/- mice fed a high-cholesterol diet and aimed to elucidate the mechanisms involved. Our results showed that TZ significantly reduced plaque size, EC senescence, vascular permeability, and reactive oxygen species (ROS) levels, effectively inhibiting atherosclerosis independently of α1-AR signaling.
In cultured primary human umbilical vein ECs (HUVECs), TZ inhibited EC senescence via the Pgk1/Hsp90 pathway. It enhanced the interaction between Hsp90 and the antioxidant enzyme peroxiredoxin 1 (Prdx1), leading to lower reactive oxygen species levels – a key driver of cellular senescence. These findings were confirmed in atherosclerotic ApoE-/- mice.
Furthermore, senescent ECs exhibited increased levels of vascular endothelial growth factor A (VEGFA) and decreased levels of angiostatin, contributing to higher vascular permeability and exacerbating atherosclerosis. TZ effectively reversed these changes.
Overall, our study demonstrates that TZ primarily alleviates EC senescence and atherosclerosis through the Pgk1/Hsp90/Prdx1 pathway, highlighting Pgk1 activation as a strategy that may also mitigate endothelial dysfunction and oxidative stress in broader cardiometabolic contexts (e.g., diabetes), suggesting that TZ is a promising senomorphic agent for treating vascular aging and that Pgk1-targeted interventions could have implications beyond atherosclerosis.
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