Senescent endothelial cells (EC) are key players in the pathophysiology of cardiovascular diseases and characterized by a reduced angiogenic and regenerative potential. Therefore, reversing EC senescence represents a promising therapeutic strategy to restore vascular integrity and increase health and lifespan. Here, we show a reversal of EC senescence following the application of a pharmacological, non-genetic, partial reprogramming strategy to induce a timely restricted induction of the Yamanaka-factors Oct3/4, Sox2, Klf4 and c-Myc (OSKM). Methods to characterize the effects of pharmacological reprogramming included the quantification of gene expression as well as functional analysis of EC in vitro . In addition, the regenerative capacity of EC was evaluated in a hind-limb ischemia model in vivo in old C57BL/6J mice. We demonstrate that the application of a pharmacological cocktail of FDA approved drugs to senescent EC resulted in a robust but timely restricted induction of OSKM (p<0.001). Additionally, siRNA-knockdown prior to the treatment confirmed the correlation between OSKM upregulation and pharmacological treatment. Induction of OSKM was associated with a significantly reduced expression of senescence markers as p16ink4a and p14arf (p<0.001). Expression of cytokines as TNFa or Il-6 was significantly reduced compared to untreated senescent cells (p<0.05). Further the telomere length was stabilized (p<0.05). We also observed enhanced functional properties of senescent EC, such as proliferation, migration, sprouting and tube formation (p<0.05). Long term cultivation of treated EC indicated that expression of p16ink4a and p14arf remained low (p<0.05), and the migratory capacity was preserved. Non-senescent EC were not influenced by the pharmacological treatment. In vivo , a significantly improved blood flow was observed after hind limb ischemia in 22 months old C57BL/6J mice after 7 and 14 days (p<0.001). Capillary density was significantly enhanced (p<0.05). In conclusion, we demonstrate that a short induction of OSKM via a pharmacological approach holds the potential to reverse senescence in EC in vitro and thus to enhance endothelial regenerative capacity in vivo . This might present a promising strategy for ischemic diseases.