Targeting p21-highly-expressing Endothelial Senescent Cells Prevent Vascular Dysfunction Induced by High-Fat Diet

BACKGROUND: Cardiovascular diseases are the leading cause of death worldwide. Overweight and obesity are strongly associated with comorbidities such as hypertension and insulin resistance, which collectively contribute to the development of cardiovascular disease. Although high-fat diet shows increased vascular senescence and vascular dysfunction, it remains unclear how obesity could induce cellular senescence and whether vascular dysfunction is associated with senescence of cells in the vasculature. p21 is one of the major regulators and most recognized cellular markers for senescent cells. Recent evidence demonstrated that high fat diet induces the accumulation of p21 high cells in the endothelial cells. However, the relationship between p21 high cells and vascular function is not identified yet. Therefore, this study investigated the linkage between vasodilation and p21 high cells in aging or high-fat diet-induced vascular dysfunction. METHODS: Five p21-Cre/+; +/+ (P) and p21-Cre/+; DTA/+ (PD) obese mice fed by high fat diet were administrated with tamoxifen for twice. Five P lean mice fed by normal chow were adopted as normal control. We previously demonstrated that p21high cells accumulate in obese P mice, and can be eliminated in obese PD mice by tamoxifen treatment. Using pressure myography, vasodilation in femoral arteries was assessed in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP). Free Radical Production were measured by Amplex Red Assays. One-way ANOVAs with Bonferroni post-hoc were used to determine differences between groups (P < 0.05). RESULTS: Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (Lean P: 62 ± 4, Obese P: 23 ± 3 %; p < 0.05) and ACh (Lean P: 77 ± 4, Obese P: 35 ± 4 %; p < 0.05). However, the clearance of p21 high cells using tamoxifen enhanced vasodilatory function response to both flow (Obese P: 23 ± 3 %, Obese PD: 58 ± 3 %; p < 0.05) and ACh (Obese P: 35 ± 4 %, Obese PD: 70 ± 3 %; p < 0.05) while endothelium-independent vasodilation was not altered by high fat diet. Also, high fat diet increased free radical production, but the clearance of p21 high cells using tamoxifen attenuated free radical production (Lean P: 10.16 ± 0.41 pmol·s-1·mg-1; Obese P: 26.83 ± 0.54 pmol·s-1·mg-1; Obese PD: 12.23 ± 0.54 pmol·s-1·mg-1; P<0.05). CONCLUSION: These results demonstrated that p21high cells may play a causal role in vascular dysfunction with obesity and other chronic disease. Therefore, targeting p21high cells may enhance vasodilatory function through decreasing oxidative stress. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.