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From the Gaubius Laboratory,*
Leiden; the Department of
Pathology,
University Hospital, Groningen; the
Department of Endocrinology,§
Leiden University
Medical Centre, Leiden; the Institute for Cardiovascular
Research,¶
Vrije Universiteit, Amsterdam, The
Netherlands; and Boehringer Mannheim,
Penzberg, Germany
Fibrin or a fibrinous exudate can facilitate angiogenesis in many
pathological conditions. In vitro, the outgrowth of
capillary-like structures in fibrin can be mimicked by exposing human
microvascular endothelial cells (hMVECs) to an angiogenic growth factor
and tumor necrosis factor (TNF)-
. Urokinase-type plasminogen
activator (u-PA) and plasmin activities are required for this
angiogenic process. This study focuses on the role and localization of
the u-PA receptor (u-PAR) in newly formed microvascular structures. The
u-PAR-blocking monoclonal antibody (MAb) H-2 completely inhibited the
formation of capillary-like tubular structures induced by exposure of
hMVECs to basic fibroblast growth factor and TNF-. This was
accompanied by a several-fold increase in u-PA accumulation in the
conditioned medium. The effect of MAb H-2 was not caused by blocking
cellular activation by u-PA/u-PAR interaction, as the
amino-terminal fragment (ATF) of u-PA, which also activates
u-PAR, prevented tube formation. In addition, the
inhibition by MAb H-2 was not due to an effect of the antibody on
u-PAR-vitronectin binding. These data show that inhibition of tube
formation can be caused not only by inhibition of u-PA or plasmin
activities but also by unavailability of the u-PAR for cell-bound
proteolysis. Immunohistochemical analysis showed that in in
vitro angiogenesis u-PAR and u-PA were localized on the
invading, tube-forming hMVECs and not on the endothelial
cells that are located on top of the fibrin matrix. u-PAR and u-PA were
also prominently expressed on endothelial cells of neovessels present
in an atherosclerotic plaque. These data may give more insight into the
role of u-PAR in repair-associated angiogenesis.
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