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Background Despite advances in the treatment of acute myocardial infarction (AMI), effective strategies to reduce ischaemia–reperfusion (IR) injury remain an unmet clinical need. The PI3K/AKT signalling pathway, or the Reperfusion Injury Salvage Kinase (RISK) pathway, has been shown to play a key role in cardioprotection across multiple preclinical models. Our previous studies identified the PI3Kα isoform as a critical mediator of this protective effect. Recently, we discovered a novel small molecule, UCL-TRO-1938 (called ‘1938’), which can enter cells and selectively activate PI3Kα, leading to significant cardioprotective effects in both mouse and rat hearts. 1 In order to investigate whether 1938 has an effect on the endothelium, we investigated the effects of 1938 on endothelial cells and vascular function.Methods and Results Western blot analysis demonstrated that treatment with 1938 significantly increased phosphorylated AKT (pAKT) levels in human umbilical vein endothelial cells (HUVECs), peaking at 15 minutes (10.1±1.1, p<0.01), with a half-life of ~4h. This activation was abrogated by co-treatment with the PI3Kα-specific inhibitor BYL719, confirming the specificity of 1938 for the PI3Kα pathway. In functional assays using an organ bath system, 1938 induced endothelium-dependent vasodilation in rat aortic rings (n=7, p<0.0001), with EC50 5.2μM. This vasodilatory effect was completely blocked by both BYL719 and the nitric oxide synthase inhibitor L-NAME, indicating that the response is mediated through the PI3Kα/AKT/eNOS/NO pathway.Conclusion 1938 activates the PI3K/AKT signalling pathway in human endothelial cells and promotes vasodilation via a PI3Kα-dependent mechanism. These findings support the potential of 1938 as a novel therapeutic candidate for improving vascular function in cardiovascular disease. Future studies aim to investigate whether the endothelial PI3K-alpha activation contributes to the cardioprotection from IRI by 1938.Reference Gong GQ, Bilanges B, Allsop B, Masson GR, Roberton V, Askwith T, Oxenford S, Madsen RR, Conduit SE, Bellini D, Fitzek M, Collier M, Najam O, He Z, Wahab B, McLaughlin SH, Chan AWE, Feierberg I, Madin A, Morelli D, Bhamra A, Vinciauskaite V, Anderson KE, Surinova S, Pinotsis N, Lopez- Guadamillas E, Wilcox M, Hooper A, Patel C, Whitehead MA, Bunney TD, Stephens LR, Hawkins PT, Katan M, Yellon DM, Davidson SM, Smith DM, Phillips JB, Angell R, Williams RL, Vanhaesebroeck B. A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Nature 2023 Jun;618(7963):159–168.