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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3637-3645
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Tissue-type plasminogen activator (t-PA) is stored
in Weibel-Palade bodies in human endothelial cells both in vitro and
in vivo
Denise Huber,
Elisabeth M. Cramer,
Jocelyne E. Kaufmann,
Paolo Meda,
Jean-Marc Massé,
Egbert
K. O. Kruithof, and
Ulrich M. Vischer
From the Division of Clinical Biochemistry and Division
of Angiology and Haemostasis, Department of Medicine, and the
Department of Morphology, Centre Médical Universitaire, Geneva,
Switzerland, and from the Department of Haematology, U474
INSERM, Hôpital Cochin and Faculté Paris-Ouest, Paris,
France.
Vascular endothelial cells are thought to be the main source of
plasma tissue-type plasminogen activator (t-PA) and von Willebrand factor (VWF). Previous studies have suggested that both t-PA and VWF
are acutely released in response to the same stimuli, both in cultured
endothelial cells and in vivo. However, the subcellular storage
compartment in endothelial cells has not been definitively established.
We tested the hypothesis that t-PA is localized in Weibel-Palade (WP)
bodies, the specialized endothelial storage granules for VWF. In
cultured human umbilical vein endothelial cells (HUVECs), t-PA was
expressed in a minority of cells and found in WP bodies by
immunofluorescence. After up-regulation of t-PA synthesis either by
vascular endothelial growth factor (VEGF) and retinoic acid or by
sodium butyrate, there was a large increase in t-PA-positive cells.
t-PA was exclusively located to WP bodies, an observation confirmed by
immunoelectron microscopy. Incubation with histamine, forskolin, and
epinephrine induced the rapid, coordinate release of both t-PA and VWF,
consistent with a single storage compartment. In native human
skeletal muscle, t-PA was expressed in endothelial cells from
arterioles and venules, along with VWF. The 2 proteins were found to be
colocalized in WP bodies by immunoelectron microscopy. These data
indicate that t-PA and VWF are colocalized in WP bodies, both in HUVECs
and in vivo. Release of both t-PA and VWF from the same storage pool likely accounts for the coordinate increase in the plasma level of the
2 proteins in response to numerous stimuli, such as physical activity,
 -adrenergic agents, and 1-deamino-8d-arginine vasopressin (DDAVP) among others.
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