Genetic Depletion of Thromboxane A2/Thromboxane-Prostanoid Receptor Signalling Prevents Microvascular Dysfunction in Ischaemia/Reperfusion Injury.

OBJECTIVE: Activation of thromboxane A₂ synthase (TXAS)/thromboxane A₂ (TXA₂)/thromboxane prostanoid (TP) receptor leads to arterial constriction, platelet aggregation and vascular injury. We attempted to characterize the microvascular dysfunction in ischaemia/reperfusion injury using genetically modified TXAS^-/-, TP^-/- and TXAS^-/-TP^-/- mice. APPROACH AND RESULTS: The cardiac micro-circulation and electrocardiograms were evaluated from B6, TXAS^-/-, TP^-/- and TXAS^-/-TP^-/- mice in response to intravenous saline, endothelin-1, U46619 (a TXA₂ agonist) and myocardial ischaemia/reperfusion injury. Cardiac function was investigated with myocardial permeability, the troponin I concentration and the infarct size. Myocardial TXAS, TP, endothelial nitric oxide (NO) synthase (eNOS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOx4), 4-hydroxynonenal, interleukin (IL)-1β, cell apoptosis, coronary effluent thromboxane B₂ (TXB₂) and superoxide anions (O₂^-) and NO concentrations were measured. Mice mesenteric reactivity in response to various drugs was assessed by wire myography. In vivo fluorescent platelet adhesiveness to the mesenteric arterial endothelium after FeCl₃ stimulation was examined. In B6 mice, ischaemia/reperfusion significantly increased levels of ST-segment elevation, myocardial TXAS, TP, NOx4, IL-1β, apoptosis, coronary endothelin-1, TXB₂, O₂^- release and the infarct size, with concomitant decreases in eNOS, NO concentrations and cardiac micro-circulation. These effects were remarkably depressed in TXAS^-/-, TP^-/- and TXAS^-/-TP^-/- mice. Aspirin treatment or depletion of the TXAS, TP or TXAS/TP gene significantly attenuated the exaggerated vascular reactivity by vasoconstrictors and vasodilators and efficiently reduced platelet adhesion to the mesenteric endothelium under FeCl₃ stimulation. CONCLUSION: Inhibiting TXAS/TXA₂/TP signalling confers microvascular protection against oxidative injury in both cardiac and mesenteric arteries.

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