Published Online
on May 17, 2004

A more recent version of this article appeared on June 1, 2004

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Submitted on June 17, 2003
Revised on February 19, 2004
Accepted on April 13, 2004

In Vivo Induction of Endothelial Apoptosis Leads to Vessel Thrombosis and Endothelial Denudation. A Clue to the Understanding of the Mechanisms of Thrombotic Plaque Erosion

E. Durand MD, A. Scoazec PhD, A. Lafont PhD, J. Boddaert MD, A. Al Hajzen MD, F. Addad MD, M. Mirshahi PhD, M. Desnos MD, A. Tedgui PhD, and Z. Mallat MD, PhD^*

From Institut National de la Santé et de la Recherche Médicale, INSERM U541, and Institut Fédératif de Recherche Paris 7, Hôpital Lariboisière (S.A., B.J., T.A., M.Z.); INSERM EMI-U00-16 (D.E., L.A., A.H.A., A.F., D.M.); and INSERM E99-12 (M.M.), Paris, France.

^* To whom correspondence should be addressed. E-mail: mallat{at}larib.inserm.fr.

Background--The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis.

Methods and Results--Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated with staurosporin for 30 minutes, whereas the contralateral artery was incubated with saline and served as control. Three days later, thrombosis was evaluated angiographically and histologically. TUNEL score in the endothelial layer was significantly increased in staurosporin-treated arteries compared with controls (2.43±0.30 versus 0.93±0.44, respectively; P=0.001). Large areas of endothelial denudation were detectable in staurosporin-treated vessels, whereas endothelium integrity was almost preserved in the saline group. Vessel thrombosis occurred in 58% of staurosporin-treated arteries (7 of 12) but in only 8% of saline-treated segments (P<0.01). Immunoreactivities for tissue factor, platelets, and fibrin were detectable within the thrombus. Addition of ZVAD-fmk (0.1 mmol/L) significantly reduced the occurrence of thrombosis (1 of 7 arteries or 14%, P=0.04). These results were confirmed in balloon-injured atheromatous arteries.

Conclusions--In vivo induction of endothelial apoptosis leads to both vessel thrombosis and endothelial denudation. Endothelial apoptosis may be a critical step in the transition from a stable endothelialized plaque to plaque erosion and thrombosis.

Key words: endothelium • apoptosis • atherosclerosis • thrombosis

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