Extracellular Vesicles Link Cerebral Ischemia to Coronary Microvascular Dysfunction - Role for RGD Motif-Activated Endothelin Signaling

Ischemic stroke is associated with increased risk of subsequent cardiac ischemic events, yet mechanisms linking cerebral ischemia to coronary dysfunction remain unclear. We hypothesized that ischemic stroke directly impairs coronary microvascular function through circulating factors released after cerebral ischemia. We found that the vasodilator function of coronary arterioles (CA) was reduced in patients with prior ischemic stroke. In rats, transient middle cerebral artery occlusion impaired CA vasodilator function. Extracellular vesicles (EVs) isolated after cerebral ischemia and delivered into the rat CA lumen also impaired vasodilation. Moreover, we found that luminal delivery of RGD peptide attenuated flow-induced vasodilation in rat CA, an effect that was prevented by BQ-123, an endothelin ETA receptor antagonist. We propose that ischemic stroke directly induces coronary microvascular dysfunction via circulating EV-mediated, RGD-motif-dependent activation of endothelin signaling. This brain-heart vascular axis provides a mechanistic basis for increased post-stroke coronary risk and identifies EV-mediated pathways as potential therapeutic targets.