Selective EPAC1 activators enhance endothelial function in models of vascular inflammation

Vascular inflammation drives the progression of atherosclerosis and related cardiovascular disorders by impairing endothelial function. Here, we examine the role of EPAC1 - a cAMP-responsive sensor protein - in modulating vascular inflammation and injury using both in vitro and ex vivo models. Data from single-cell RNA sequencing revealed that EPAC1 is predominantly localised in endothelial cells within the media-intimal layer of healthy murine aortae, with expression increased in atherosclerotic vessels. Complementary findings in atherosclerotic human coronary arteries confirm EPAC1's endothelial presence. EPAC1 activation is known to suppress IL-6-mediated pro-inflammatory responses via upregulation of SOCS3, and inhibition of the JAK/STAT3 signalling pathway. Here, ex vivo treatment of naïve aortic rings with IL-6 and its soluble receptor (sIL-6R) significantly impaired acetylcholine-induced, nitric oxide (NO)-mediated relaxation. EPAC1 activators, SY007 (EC₅₀ = 300 nM) and D-007 (EC₅₀ = 6.76 µM), effectively restored endothelial function, while endothelium-independent responses to sodium nitroprusside were unaffected. In an aortic ring model of vascular injury, IL-6 induced substantial cellular outgrowth, which was notably reduced by the EPAC1 activator, PWO577; EPAC1 knockout mice exhibited enhanced outgrowth, emphasizing EPAC1's role in restraining stromal cell proliferation. Furthermore, in a three-cell co-culture system, comprising human vascular endothelial, smooth muscle and macrophage cells, EPAC1 activators induced transcriptional reprogramming in endothelial cells, upregulating eNOS (NOS3) and downregulating pro-inflammatory mediators. These results highlight the therapeutic potential of selective EPAC1 activation for restoring endothelial function and mitigating vascular inflammation.