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Steffen Massberg^*, Matthias Sausbier, Peter Klatt, Markus Bauer, Alexander Pfeifer, Wolfgang Siess, Reinhard Fässler^||, Peter Ruth, Fritz Krombach^*, and Franz Hofmann

From the ^* Institut für Chirurgische Forschung der Ludwig-Maximilians-Universität München, 81377 München, Germany; the Institut für Pharmakologie und Toxikologie der Technische Universität München, 80802 München, Germany; the Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Klinikum Innenstadt, Universität München, 80336 München, Germany; and the ^|| Department of Experimental Pathology, Lund University, 221 85 Lund, Sweden

Atherosclerotic vascular lesions are considered to be a major cause of ischemic diseases, including myocardial infarction and stroke. Platelet adhesion and aggregation during ischemia–reperfusion are thought to be the initial steps leading to remodeling and reocclusion of the postischemic vasculature. Nitric oxide (NO) inhibits platelet aggregation and smooth muscle proliferation. A major downstream target of NO is cyclic guanosine 3',5'-monophosphate kinase I (cGKI). To test the intravascular significance of the NO/cGKI signaling pathway in vivo, we have studied platelet–endothelial cell and platelet–platelet interactions during ischemia/reperfusion using cGKI-deficient (cGKI^–/–) mice. Platelet cGKI but not endothelial or smooth muscle cGKI is essential to prevent intravascular adhesion and aggregation of platelets after ischemia. The defect in platelet cGKI is not compensated by the cAMP/cAMP kinase pathway supporting the essential role of cGKI in prevention of ischemia-induced platelet adhesion and aggregation.

Key Words: fluorescence microscopy • endothelial cell • microcirculation • nitric oxide • cyclic guanosine 3',5'-monophosphate–dependent protein kinase

S. Massberg and M. Sausbier contributed equally to this work.

Abbreviations used: cAK, cAMP-dependent protein kinase; cGKI, cGMP-dependent protein kinase I; cGMP, cyclic guanosine 3',5'-monophosphate; I/R, ischemia/reperfusion; NO, nitric oxide; PRP, platelet-rich plasma; VASP, vasodilator-stimulated phosphoprotein.

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