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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1632.)
© 2006 American Heart Association, Inc.

Thrombosis

Local Heat Shock Priming Promotes Recanalization of Thromboembolized Microvasculature by Upregulation of Plasminogen Activators

Martin Rücker; Thilo Schäfer; Claudia Scheuer; Yves Harder; Brigitte Vollmar; Michael D. Menger

From the Institute for Clinical & Experimental Surgery (M.R., T.S., C.S., Y.H., M.M.), University of Saarland, Homburg/Saar; the Department of Oral and Maxillofacial Surgery (M.R.), Hannover Medical School, Hannover; and the Department of Experimental Surgery (B.V.), University of Rostock, Rostock, Germany.

Correspondence to Michael D. Menger, MD, Institute for Clinical & Experimental Surgery, University of Saarland, D-66421 Homburg/Saar, Germany. E-mail exmdme{at}uniklinik-saarland.de

Objective— Thromboembolization and subsequent microvascular perfusion failure is implicated in the pathology of a variety of diseases, including transient ischemic attack (TIA), stroke, and myocardial infarction, and also for the complications after interventional and microsurgical procedures in coronary heart disease and peripheral arterial occlusive disease. In vitro heat shock priming has been suggested to induce plasminogen activators, which are the major upregulators of the fibrinolytic system. Herein, we determined whether local heat shock priming endogenously upregulates plasminogen activators also in vivo, and whether this promotes recanalization of thromboembolized microvasculature.

Methods and Results— To induce thromboembolization, a suspension of preformed microthrombi (maximum diameter: 40 µm) was injected via the femoral artery into the left hindlimbs of anesthetized rats. Local heat shock priming (42.5°C, 30 minutes) was performed 24 hours before embolization and resulted in a significant increase of endothelium-derived plasminogen activator expression. The study of the microcirculation by intravital microscopy revealed in all tissues analyzed (muscle, periosteum, subcutis, and skin) that heat shock priming significantly (P<0.05) accelerates recanalization of the thromboembolized microvasculature when compared with nonprimed and sham-primed controls. Importantly, the addition of plasminogen activator inhibitor-1 to the microthrombi suspension completely blunted the heat shock-induced acceleration of microvascular recanalization.

Conclusions— Heat shock induces endogenous hyperfibrinolysis by upregulation of plasminogen activators that promote recanalization of thromboembolized microvasculature.

Using a rat thromboembolization model and intravital fluorescence microscopy, this study demonstrates that heat shock priming induces endothelium-derived plasminogen activator expression in vivo, and accelerates spontaneous recanalization of thromboembolized microvasculature. This was completely blunted by application of plasminogen activator inhibitor-1. Thus, heat shock induces endogenous hyperfibrinolysis, which promotes recanalization of thromboembolized microvasculature.

Key Words: heat shock • intravital microscopy • microcirculation • plasminogen activator inhibitor-1 • thromboembolization • urokinase plasminogen activator

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