Abstract EN:

Recombinant tissue-type plasminogen (rtPA) is the only treatment approved so far for acute ischemic stroke. However, clinical investigations have evidenced that number of clots are resistant to rtPA-induced thrombolysis. To improve the efficacy of rtPA-mediated thrombolysis, the aims of the present work were (i) to compare rtPA-induced recanalization in animal stroke models mimicking two etiologies such as thromboembolic and in situ thrombosis (ii) to understand the molecular mechanisms involved in formation of rtPA-resistant thrombi (iii) to improve clot lysis by targeting platelet receptors and (iv) to study the impact of molecules involved in the degradation of the extracellular matrix on the integrity of the blood brain barrier (BBB) following stroke. Our results confirm that the sensitivity to rtPA-mediated thrombolysis is influenced by thrombus composition and etiology. We demonstrated for the first time that occlusive thrombus formation is a two-steps mechanism: partial occlusion of the blood vessel depends on platelet aggregation through their glycoproteins (Gp) IIb/IIIa receptors and vessel lumen closure involves the GpIbα receptors. Thus, inhibitors of the GpIbα-vWF axis induce specific dissolution of the last-formed platelet aggregates and restore vessel patency. In ischemic conditions, early disruption of the clot is needed for minimizing cerebral damages but maintaining the BBB integrity is also crucial. Our results suggest that the metalloproteinase ADAMTS-4 that degrades the extracellular matrix is involved in maintaining the integrity of the BBB. Thus, ADAMTS-4 and GpIbα-VWF are promising candidates to minimize cerebral damages following ischemic stroke.