Selective EPAC1 activators enhance endothelial function in models of vascular inflammation

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Signaling

Background:

• Vascular inflammation and endothelial dysfunction are central to atherosclerosis progression.
• EPAC1 (cAMP-responsive sensor protein) is implicated in cellular responses to inflammation.
• Understanding EPAC1's role is crucial for developing therapies against cardiovascular disorders.

Purpose of the Study:

• To investigate the role of EPAC1 in modulating vascular inflammation and injury.
• To assess the therapeutic potential of EPAC1 activation in restoring endothelial function.

Main Methods:

• Single-cell RNA sequencing to determine EPAC1 localization in murine and human arteries.
• Ex vivo studies using aortic rings to evaluate endothelial function and vascular injury.
• In vitro three-cell co-culture system (endothelial, smooth muscle, macrophage cells) to analyze transcriptional changes.

Main Results:

• EPAC1 is localized in endothelial cells and its expression increases in atherosclerotic vessels.
• EPAC1 activators restored nitric oxide-mediated relaxation impaired by IL-6.
• EPAC1 activation reduced cellular outgrowth in vascular injury models and reprogrammed endothelial cells to an anti-inflammatory phenotype.

Conclusions:

• EPAC1 plays a protective role in vascular inflammation and injury.
• Selective EPAC1 activation demonstrates therapeutic potential for atherosclerosis and cardiovascular diseases.
• Targeting EPAC1 may restore endothelial function and mitigate vascular inflammation.