Published online before print November 21, 2002, doi: 10.1161/01.RES.0000048196.11060.A0
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Submitted on October 4, 2002
Revised on November 8, 2002
Accepted on November 11, 2002
Wall Tension Is a Potent Negative Regulator of In Vivo Thrombomodulin Expression
Jason L. Sperry ;
From the Division of Cardiology (C.B., C.B.D., D.A.K., A.Y.K., J.J.R.), Department of Surgery (J.L.S., P.L.W.) of the Johns Hopkins School of Medicine, Baltimore, Md; and the Armed Forces Institute of Pathology (F.D.K., R.V.), Washington, DC.
* To whom correspondence should be addressed. E-mail: jjrade{at}jhmi.edu.
Thrombomodulin (TM), a key component of the anticoagulant protein C pathway, is a major contributor to vascular thromboresistance. We previously found that TM protein expression is dramatically reduced in autologous vein grafts during the first two weeks after implantation, coincident to a local inflammatory response, and remains suppressed for at least 6 weeks. To determine the proximate cause of TM loss, in vivo gene expression was quantified by real-time PCR. TM gene expression in vein grafts declined >85% during the first postoperative week and remained suppressed >55% at 6 weeks, accounting for the observed changes in protein expression. The effects of vein graft inflammation were evaluated in animals rendered leukopenic with vinblastine before graft implantation. Abrogating the local inflammatory response affected neither TM protein nor gene expression. To determine how hemodynamic forces might modulate TM expression, the surgical protocol was modified to alter blood flow and pressure-induced vessel distension. TM protein and gene expression did not correlate to changes in shear stress but highly correlated to changes in wall tension, both acutely and over time. We conclude that the primary stimulus for altered TM expression in vein grafts is the exposure to arterial pressure. Furthermore, these data identify strain as a novel and important pathway for in vivo TM gene regulation.
Key words: thrombomodulin • wall tension • shear stress • thrombosis • vein graft
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