Vascular protection through humoral factors released by RIC

Research on the pathophysiological mechanisms of myocardial ischemia/reperfusion (IR) injury has predominantly focused on cardiomyocyte injury. However, myocardial IR also induces vascular injury, particularly in the coronary microcirculation, e.g. myocardial edema cause extravascular compression and endothelial and vascular smooth muscle cell dysfunction impairs vasomotor function, which further exacerbates myocardial damage. In patients with acute myocardial infarction, microvascular obstruction determines patient prognosis, independent of infarct size. Remote ischemic conditioning (RIC), brief episodes of IR in the limbs, is a noninvasive strategy that reduces not only infarct size but also seems to have an effect on myocardial edema in experimental models as well as in patients. RIC´s signal transfer from periphery to the heart is mediated through neuronal and humoral signaling. Thus, cardioprotection by RIC is transferable from one species to another via blood plasma to isolated cardiomyocytes and ex vivo isolated perfused hearts from RIC-conditioned donors. However, it is unclear whether RIC also protects the coronary vasculature. Thus, we aim to determine whether the humoral factors released by RIC have also a vascular protective potential. In healthy human volunteers (30 ± 10 years; 6F, 8M), RIC was induced by three cycles of 5/5 min IR in one upper limb with a blood pressure cuff (200 mmHg), blood samples were collected before and 60 min after RIC. Plasma supernatant was separated after centrifugation (× 800 g / 15 min, × 4500 g / 10 min) of the blood samples. Rat coronary arteries were isolated post-mortem and were mounted on a small vessel wire myograph for isometric force measurement. All arteries were tested for functionality (depolarization of vascular smooth muscle cells by potassium chloride, 60 mM and 120 mM) and endothelial integrity (endothelium-dependent relaxation to carbachol, 1 × 10-4 M, after pre-constriction to serotonin, 3 × 10-6 M). Then, the arteries were subjected to either simulated IR (sIR, 60 min hypoxia / 10 min reoxygenation) or a corresponding normoxic time control (TC). In the first set of experiments, we confirmed the prior described endothelium-dependent IR injury in coronary arteries via increase of half maximal effective concentration (EC50) after pre-constriction with serotonin (3 × 10-6 M) in response to carbachol (1 × 10-9 M - 1 × 10-4 M) of ~35%. In the second set of experiments, the coronary arteries were subjected to either sIR or TC in presence (60 min) of plasma collected before RIC (boforeRIC) or after RIC (afterRIC), again, EC50 in response to carbachol were determined. Arteries in all 4 groups (sIR + beforeRIC, sIR + afterRIC, TC + beforeRIC, TC + afterRIC) had comparable vasomotor function and the extent of pre-constriction was also comparable. For TC arteries, the EC50 was comparable between beforeRIC and afterRIC (3.89 × 10-7 ± 2.48 × 10-7 M; 3.60 × 10-7 ± 2.42 × 10-7 M). For arteries with beforeRIC plasma, the EC50 was higher after sIR versus TC (7.14 × 10-7 ± 5.28 × 10-7 M versus 3.89 × 10-7 ± 2.48 × 10-7 M), confirming the endothelium-dependent injury after sIR. Interestingly, in the sIR groups, the EC50 was lower with afterRIC plasma (4.50 × 10-7 ± 2.78 × 10-7 M). In conclusion, humoral factors, released by RIC, not only reduce cardiomyocyte IR injury but also reduce vasomotor dysfunction induced by sIR. Future investigations are needed to confirm this vascular protective effects in coronary arterioles and in coronary microcirculation. Further, underlying signaling pathways, involved in the vascular protection by RIC, should be identified. X.Z., M.A., C.E. and P.K. acknowledge the support by the DFG (RTG 2989 P5) and C.E. by the DGK (DGK05/2025). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.