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(Circulation. 1997;96:3888-3896.)
© 1997 American Heart Association, Inc.

Articles

Aggregating Human Platelets Stimulate the Expression of Thrombin Receptors in Cultured Vascular Smooth Muscle Cells via the Release of Transforming Growth Factor-ß₁ and Platelet-Derived Growth Factor_AB

Valérie B. Schini-Kerth, PhD; Steffen Bassus; Beate Fisslthaler, PhD; Carl M. Kirchmaier, MD; ; Rudi Busse, MD, PhD

From the Institut für Kardiovaskuläre Physiologie, Klinikum der JWG-Universität (V.B.S.-K., B.F., R.B.) and Blutspendedienst Hessen (S.B., C.M.K.), Frankfurt am Main (Germany).

Background Thrombin and the thrombin receptor have been implicated in the proliferation of vascular smooth muscle cells (VSMCs) observed after angioplasty and in atherosclerosis. Because thrombin receptor activation is an irreversible proteolytic event, the marked upregulation of the smooth muscle cell thrombin receptor after vascular injury may account for the maintained mitogenic activity of thrombin. The present study was designed to determine whether aggregating platelets stimulate thrombin receptor expression in cultured VSMCs and, if so, to identify the mediators.

Methods and Results Thrombin receptor expression was assessed by Northern and Western blot analyses and functionally by measuring the release of 6-keto prostaglandin F₁. Platelet-derived products (PDPs) released by aggregating human platelets enhanced thrombin receptor mRNA levels in a time- and concentration-dependent manner, an effect that was potentiated by transient acidification of PDPs, which release bioactive transforming growth factor (TGF)-ß₁, and that was slightly inhibited by ketanserin. Among several factors known to be released by aggregating platelets, only TGF-ß₁, platelet-derived growth factor_AB (PDGF_AB), and serotonin mimicked the PDP effect. The level of membrane thrombin receptor protein was increased in TGF-ß₁–treated VSMCs. Pretreatment of VSMCs with either acidified PDP, or TGF-ß₁ increased the -thrombin–stimulated release of 6-keto prostaglandin F₁. This effect was blunted by incubating acidified PDP with either a TGF-ß–or a PDGF-neutralizing antibody.

Conclusions Aggregating human platelets stimulate the expression of thrombin receptors in VSMCs through the release of TGF-ß₁, PDGF_AB, and, to a lesser extent, serotonin. The upregulation of the thrombin receptor by products released by aggregating platelets may sustain the mitogenic activity of thrombin in the vascular wall at sites of injury.

Key Words: platelet-derived factors • receptors • thrombin • muscle, smooth • arteriosclerosis

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