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Hypoxia Stimulates Urokinase Receptor Expression Through a Heme
Protein-Dependent Pathway
Charles H. Graham,
Tania E. Fitzpatrick, and
Keith R. McCrae
From the Department of Anatomy and Cell Biology, Queen's University,
Kingston, Ontario, Canada; and the Sol Sherry Thrombosis Research
Center, Temple University School of Medicine, Philadelphia, PA.
Hypoxia underlies a number of biologic processes in which cellular
migration and invasion occur. Because earlier studies have shown that
the receptor for urokinase-type plasminogen activator (uPAR) may
facilitate such events, we studied the effect of hypoxia on the
expression of uPAR by first trimester human trophoblasts (HTR-8/SVneo)
and human umbilical vein endothelial cells (HUVEC). Compared with
control cells cultured under standard conditions (20% O2),
HTR-8/SVneo cells and HUVEC cultured in 1% O2 expressed more uPAR, as determined by flow cytometric and
[125I]-prourokinase ligand binding analyses. Increased
uPAR expression paralleled increases in uPAR mRNA. The involvement of a
heme protein in the hypoxia-induced expression of uPAR was suggested by
the observations that culture of cells with cobalt chloride, or sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron), an iron-chelating agent,
also stimulated uPAR expression, and that the hypoxia-induced uPAR
expression was inhibited by adding carbon monoxide to the hypoxic
atmosphere. Culture of HTR-8/SVneo cells with vascular endothelial
growth factor (VEGF) did not increase uPAR mRNA levels, suggesting that
the hypoxia-mediated effect on uPAR expression by these cells did not
occur through a VEGF-dependent mechanism. The functional importance of
these findings is suggested by the fact that HTR-8/SVneo cells cultured
under hypoxia displayed higher levels of cell surface plasminogen
activator activity and greater invasion through a reconstituted
basement membrane. These results suggest that hypoxia may promote
cellular invasion by stimulating the expression of uPAR through a heme
protein-dependent pathway.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3300-3307
© 1998 by The American Society of Hematology.
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