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 = 300nM) and D-007 (EC50 = 6.76µM), 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.
MacRitchie et al. (Thu,) studied this question.
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