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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 927-938
Effect of Steroid Hormones and Retinoids on the Formation of
Capillary-Like Tubular Structures of Human Microvascular Endothelial
Cells in Fibrin Matrices Is Related to Urokinase Expression
Mirian Lansink,
Pieter Koolwijk,
Victor van Hinsbergh, and
Teake Kooistra
From the Gaubius Laboratory TNO-PG, Leiden, The Netherlands.
Angiogenesis, the formation of new capillary blood vessels, is a
feature of a variety of pathological processes. To study the effects of
a specific group of hormones (all ligands of the steroid/retinoid/thyroid hormone receptor superfamily) on the angiogenic process in humans, we have used a model system in which human microvascular endothelial cells from foreskin (hMVEC) are cultured on top of a human fibrin matrix in the presence of basic fibroblast growth factor and tumor necrosis factor- . This model mimics the in vivo situation where fibrin appears to be a common component of the matrix present at sites of chronic inflammation and
tumor stroma. Our results show that testosterone and dexamethasone are
strong inhibitors and all-trans retinoic acid (at-RA)
and 9-cis retinoic acid (9-cis RA) are potent
stimulators of the formation of capillary-like tubular structures.
These effects are mediated by their respective nuclear hormone
receptors as demonstrated by the use of specific synthetic receptor
agonists and antagonists. 17 -estradiol, progesterone, and
1,25-dihydroxyvitamin D3 did not affect or only weakly affected in
vitro angiogenesis, which may be related to the lack of significant
nuclear receptor expression. Although hMVEC express both thyroid
hormone receptors and , no effect of thyroid hormone on tube
formation was found. The effects of testosterone, dexamethasone,
at-RA, and 9-cis RA on tube formation were accompanied
by parallel changes in urokinase-type plasminogen activator (u-PA)
expression, at both mRNA and antigen levels. Exogenous suppletion of
the medium with single chain u-PA enhances tube formation in our in
vitro model, whereas quenching of u-PA activity (but not of tissue-type
plasminogen activator activity) or of u-PA binding to u-PA receptor by
specific antibodies suppressed basal and retinoid-stimulated tube
formation. Moreover, addition of scu-PA to testosterone- or
dexamethasone-treated hMVEC restored the suppressed angiogenic activity
for a substantial part. Aprotinin, an inhibitor of plasmin activity,
completely inhibited tube formation, indicating that the proteolytic
properties of the u-PA/u-PA receptor complex are crucial in this
process. Our results show that steroid hormones (testosterone and
dexamethasone) and retinoids have strong, but opposite effects on tube
formation in a human in vitro model reflecting pathological
angiogenesis in the presence of fibrin and inflammatory mediators.
These effects can be explained by hormone-receptor-mediated changes in
u-PA expression, resulting in enhanced local proteolytic capacity of the u-PA/u-PA receptor complex.
© 1998 by The American Society of Hematology.
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