Abstract Body: Introduction: Endothelial progenitor cells (EPCs) play a critical role in vascular repair by replenishing damaged endothelium and resolving inflammation. In hypertension, EPCs may lose their reparative capacity. While mechanical forces are known to regulate endothelial function, their impact on EPCs remains unclear. Hypothesis: We hypothesize that sustained hypertensive-like mechanical stretch induces EPC dysfunction by promoting senescence, mitochondrial impairment via loss of mitofusin-2 (Mfn2), and altered expression of the pro-resolving receptor formyl peptide receptor-2 (FPR-2). Ultimately, this leads to EPC exhaustion and their disappearance in established hypertension. Methods: En face immunofluorescence (IF) was performed on the aortic arch of normotensive C57BL/6 and BPN/3J, and hypertensive BPH/2J mice. Murine aortic arch EPCs were subjected to 24-hour mechanical stretch (5% or 19%) or static conditions. β-galactosidase (Glb1) and Mfn2 levels were assessed by RTq-PCR. FPR-2 expression was evaluated by IF. Statistical analysis: One-way ANOVA, Tukey post-hoc (p<0.05). Results: Normotensive mice harbored CD117+ and Sca-1+ EPCs, while hypertensive BPH mice lacked Sca-1+ and CD117+ cells, indicating EPC depletion in chronic hypertension. In vitro, EPCs exposed to hypertensive-like stretch (19%) showed an increase in their progenitor marker Sca-1 (IF AU: Static: 3801±430 vs. 5%: 5236±1139 vs. 19%: 7067±1171*; *p=0.055). These cells also displayed increased Glb1 expression (Fold change/18S: Static: 1±0.08* vs. 5%: 0.43±0.12 vs. 19%: 1.1±0.03*, *p<0.05) and reduced Mfn2 levels (Fold change/18S: Static: 1±0.18 vs. 5%: 0.22±0.09* vs. 19%: 0.1±0.01*, *p<0.05), suggesting a shift toward senescence and decreased mitochondrial fusion. FPR-2 expression was upregulated under hypertensive-like stretch (IF AU: Static: 5743±727 vs. 5%: 4835±774 vs. 19%: 10729±1328*; *p=0.055), particularly with prominent nuclear localization. Conclusion: Our data demonstrates that sustained hypertensive-like stretch activates EPCs and FPR-2, potentially as a reparative response. Ultimately it drives EPC exhaustion through mfn2 loss and senescence. In established hypertension, EPC depletion from the endothelium suggests a failure of the repair mechanism, contributing to vascular remodeling. These findings highlight the vulnerability of EPCs to mechanical stress and identify them as potential targets for therapeutic strategies to preserve vascular homeostasis in hypertension.