Me. Kroon et al., Role and localization of urokinase receptor in the formation of new microvascular structures in fibrin matrices, AM J PATH, 154(6), 1999, pp. 1731-1742
Citations number
59
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Fibrin or a fibrinous exudate can facilitate angiogenesis in many pathologi
cal conditions. In vitro, the outgrowth of capillary-like structures in fib
rin can be mimicked by exposing human microvascular endothelial cells (hMVE
Cs) to an angiogenic growth factor and tumor necrosis factor (TNF)-alpha. U
rokinase-type plasminogen activator (u-PA) and plasmin activities are requi
red for this angiogenic process. This study focuses on the role and localiz
ation 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 hMVE
Cs to basic fibroblast growth factor and TNF-alpha. This was accompanied by
a several-fold increase in u-PA accumulation in the conditioned medium. Th
e effect of MAb H-2 was not caused by blocking cellular activation by u-PA/
u-PAR interaction, as the aminoterminal fragment (ATF) of u-PA, which also
activates u-PAR, prevented tube formation. In addition, the inhibition by M
Ab H-2 was not due to an effect of the antibody on u-PAR-vitronectin bindin
g. 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 t
hat 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 t
op 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 ang
iogenesis.