Menstrual Cycle Influences the Protective Effects of Remote Ischemic Preconditioning Against Endothelial Ischemia‐Reperfusion injury

Abstract

PURPOSEA promising therapeutic intervention to counteract endothelial ischemia/reperfusion (I/R) injury is ischemic preconditioning (IPC). Limited data from ovariectomized animal models shows that estrogen deficiency abolishes the cardioprotective effects of IPC, whereas estrogen replacement restores protection. This suggests that alterations in female sex hormones, particularly estrogens, that occur naturally during the menstrual cycle is likely to influence the vascular protective properties of IPC. The aim of the present study was to identify how changes in female sex hormones that occur naturally during the menstrual cycle interfere with IPC to provide vascular endothelial protection in women.METHODSTen healthy premenopausal eumenorrheic women (age 21±1 yr) not taking any contraceptive medications were studied in a within‐subjects design. Primary outcomes with respect to the assessment of vascular endothelial function were measured during the early follicular (after onset of menses; days 1–6) and at mid‐cycle during ovulation (days 10–14 after positive urine ovulation test). Endothelium‐dependent vasodilation was assessed by the forearm blood flow (FBF) response to reactive hyperemia using strain‐gauge venous occlusion plethysmography in the absence and presence of endothelial I/R injury (20 min brachial artery ischemia followed by 15 min reperfusion) when preceded by remote IPC (right arm: 3×5 min cycles of ischemia).RESULTSIn the absence of endothelial I/R injury, peak FBF to reactive hyperemia was similar (P=0.19) between the early follicular (19.9±6.1 ml/100ml tissue/min) and ovulation phases (22.1±5.9 ml/100ml tissue/min). In contrast, there was a significant main effect (P=0.001) of menstrual cycle phase on the capacity of IPC to protect against endothelial I/R injury. For example, during the early follicular phase, peak FBF was significantly (P=0.02) diminished with endothelial I/R injury (from: 19.9±6.1 to 17.1±4.1 ml/100ml tissue/min) despite remote IPC. As a result, total FBF during the initial 30 sec of reactive hyperemia (area under the curve) was decreased ~18% (P=0.027) after (41.0±11.4 ml/100ml tissue) compared with before (49.6±15.1 ml/100ml tissue) endothelial I/R injury. However, during ovulation, remote IPC provided a level of endothelial protection from I/R injury that was not observed in the early follicular phase. With endothelial I/R injury, peak FBF increased 15% (from: 22.1±5.9 to 25.3±6.4 ml/100ml tissue/min; P=0.012). As a result, total FBF was well preserved (P=0.859) after (58.2±14.6 ml/100ml tissue) compared with before (58.0±13.3 ml/100 ml tissue) endothelial I/R injury.CONCLUSIONSThese data suggest that the menstrual cycle differentially influences the capacity of remote IPC to protect against endothelial I/R injury. Greater circulating estrogens during ovulation may be an important mediator contributing to the protective benefits of remote IPC in women.Support or Funding InformationSouth Dakota State University Research Scholarship Support Fund