Senolytic Treatment with Dasatinib and Quercetin Improves Endothelial Function in Old Mice

Advanced age is associated with an increased risk of cardiovascular disease (CVD). Small arteries and the endothelium are particularly susceptible to age-related dysfunction, which impairs tissue perfusion and contributes to increased CVD risk. The endothelial glycocalyx, a gel-like structure bound to the luminal surface, is crucial to maintaining barrier integrity and microcirculatory health. Degradation of the glycocalyx increases vascular permeability and inflammation and promotes vascular aging. Endothelial cells (ECs) are central to vascular homeostasis, regulating vasodilation and modulating inflammation. ECs synthesize and release the pro-vasodilatory and vasoprotective molecule nitric oxide (NO), which reduces oxidative stress and limits atherogenesis. Cellular senescence is a state of stable cell cycle arrest, characterized by elevated production of reactive oxygen species (ROS) and various inflammatory markers and growth factors collectively known as the senescence-associated secretory phenotype (SASP). With age, accumulation of senescent ECs contributes to impaired NO signaling, increased oxidative stress, and inflammation, which compromise microvascular integrity. Senolytic drugs selectively eliminate senescent cells and lower SASP burden. They have the potential to ameliorate endothelial and vascular function by improving the cellular milieu and increasing EC proliferation. We hypothesized that senolytic treatment with dasatinib plus quercetin (D+Q) would improve endothelial-dependent dilation (EDD), glycocalyx thickness, and EC proliferation. Old male C57BL/6 mice (21 months old) were treated with a senolytic drug cocktail consisting of D (5 mg/kg) and Q (50 mg/kg), or vehicle (V), on three consecutive days every two weeks for three months. Using pressure myography, EDD was assessed in response to increasing doses of the vasodilator acetylcholine (ACh) in the absence and presence of the NO synthase inhibitor L-NAME. Arteries were then incubated with the superoxide scavenger TEMPO, and the ACh responses were repeated. Perfused boundary region (PBR), a metric that reflects capillary barrier integrity, in the mesenteric microcirculation was evaluated using intravital microscopy with an automated capture and analysis system (Glycocheck). Lung ECs were isolated from both groups of mice, and EC proliferation was measured using electric cell-substrate impedance sensing technology. D+Q-treated mice showed a greater EDD to ACh compared to V mice (p< 0.005). Group differences in EDD were abolished with L-NAME, suggesting that treatment with D+Q improved the NO-dependent vasodilation in the old mice. Compared to V mice, NO bioavailability tended to be higher (p=0.07) in arteries from D+Q mice. TEMPOL improved EDD in arteries from V mice (p< 0.05) but had no effect in arteries from D+Q mice. PBR tended to be lower in D+Q-treated mice (2.01±0.05) compared to V mice (2.17±0.06; p=0.06), indicating decreased glycocalyx permeability. Lung ECs from D+Q mice exhibited a higher proliferative capacity (2.40±0.07) compared to V mice (1.97±0.05; p< 0.01). In summary, treatment with D+Q improved EDD, glycocalyx integrity and barrier function, and EC proliferation in aged mice. Further, the improved EDD and NO bioavailability with D+Q appears to be mediated, in part, by reductions in oxidative stress. The data herein suggest that senolytic treatment can ameliorate endothelial and vascular dysfunction associated with advanced age. These results highlight the therapeutic potential of D+Q to mitigate vascular aging and reduce CVD risk by targeting senescent cells. Funding sources The Nora Eccles Treadwell Foundation; T NIA 1K08AG070281LAL R01AG076748TJD R01AG077751 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.