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Blood, 15 October 2000, Vol. 96, No. 8, pp. 2775-2783
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Urokinase receptor expression on human microvascular
endothelial cells is increased by hypoxia: implications for
capillary-like tube formation in a fibrin matrix
Marielle E. Kroon,
Pieter Koolwijk,
Bea van der
Vecht, and
Victor W. M. van
Hinsbergh
From the Gaubius Laboratory TNO-PG, Leiden, The
Netherlands, and the Institute for Cardiovascular Research, Vrije
Universiteit, Amsterdam, The Netherlands.
Hypoxia stimulates angiogenesis, the formation of new blood
vessels. This study evaluates the direct effect of hypoxia (1% oxygen)
on the angiogenic response of human microvascular endothelial cells
(hMVECs) seeded on top of a 3-dimensional fibrin matrix. hMVECs
stimulated with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth factor (VEGF) together with tumor necrosis factor- (TNF-) formed 2- to 3-fold more tubular structures under hypoxic conditions than in normoxic (20% oxygen) conditions. In both
conditions the in-growth of capillary-like tubular structures into
fibrin required cell-bound urokinase-type plasminogen activator (uPA) and plasmin activities. The hypoxia-induced increase in tube
formation was accompanied by a decrease in uPA accumulation in the
conditioned medium. This decrease in uPA level was completely abolished
by uPA receptor-blocking antibodies. During hypoxic culturing uPA
receptor activity and messenger RNA (mRNA) were indeed increased. This
increase and, as a consequence, an increase in plasmin formation
contribute to the hypoxia-induced stimulation of tube formation. A
possible contribution of VEGF-A to the increased formation under
hypoxic conditions is unlikely because there was no increased VEGF-A
expression detected under hypoxic conditions, and the
hypoxia-induced tube formation by FGF-2 and TNF- was not inhibited
by soluble VEGFR-1 (sVEGFR-1), or by antibodies blocking VEGFR-2.
Furthermore, although the v-integrin subunit was
enhanced by hypoxia, blocking antibodies against
v 3- and v5-integrins had no effect on
hypoxia-induced tube formation. Hypoxia increases uPA
association and the angiogenic response of human endothelial cells in a
fibrin matrix; the increase in the uPA receptor is an important
determinant in this process.
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