AGGREGATING HUMAN PLATELETS STIMULATE THE EXPRESSION OF THROMBIN RECEPTORS IN CULTURED VASCULAR SMOOTH-MUSCLE CELLS VIA THE RELEASE OF TRANSFORMING GROWTH FACTOR-BETA(1) AND PLATELET-DERIVED GROWTH FACTOR(AB)
Vb. Schinikerth et al., AGGREGATING HUMAN PLATELETS STIMULATE THE EXPRESSION OF THROMBIN RECEPTORS IN CULTURED VASCULAR SMOOTH-MUSCLE CELLS VIA THE RELEASE OF TRANSFORMING GROWTH FACTOR-BETA(1) AND PLATELET-DERIVED GROWTH FACTOR(AB), Circulation, 96(11), 1997, pp. 3888-3896
Background Thrombin and the thrombin receptor have been implicated in
the proliferation of vascular smooth muscle cells (VSMCs) observed aft
er angioplasty and in atherosclerosis. Because thrombin receptor activ
ation is an irreversible proteolytic event, the marked upregulation of
the smooth muscle cell thrombin receptor after vascular injury may ac
count for the maintained mitogenic activity of thrombin. The present s
tudy was designed to determine whether aggregating platelets stimulate
thrombin receptor expression in cultured VSMCs and, if so, to identif
y the mediators. Methods and Results Thrombin receptor expression was
assessed by Northern and Western blot analyses and functionally by mea
suring the release of 6-keto prostaglandin F-1 alpha. Platelet-derived
products (PDPs) released by aggregating human platelets enhanced thro
mbin receptor mRNA levels in a time-and concentration-dependent manner
, an effect that was potentiated by transient acidification of PDPs, w
hich release bioactive transforming growth factor (TGF)-beta(1), and t
hat was slightly inhibited by ketanserin. Among several factors known
to be released by aggregating platelets, only TGF-beta(1), platelet-de
rived growth factor(AB) (PDGF(AB)), and serotonin mimicked the PDP eff
ect. The level of membrane thrombin receptor protein was increased in
TGF-beta(1)-treated VSMCs. Pretreatment of VSMCs with either acidified
PDP, or TGF-beta(1) increased the alpha-thrombin-stimulated release o
f 6-keto prostaglandin F-1 alpha. This effect was blunted by incubatin
g acidified PDP with either a TGF-beta-or a PDGF-neutralizing antibody
. Conclusions Aggregating human platelets stimulate the expression of
thrombin receptors in VSMCs through the release of TGF-beta(1), PDGF(A
B) and, to a lesser extent, serotonin. The upregulation of the thrombi
n receptor by products released by aggregating platelets may sustain t
he mitogenic activity of thrombin in the vascular wall at sites of inj
ury.