Paracrine Stimulation of Capillary Endothelial Cell Migration by Endometrial Tissue Involves Epidermal Growth Factor and Is Mediated Via Up-Regulation of the Urokinase Plasminogen Activator Receptor
Tove Sandberg,
Anna Ehinger and
Bertil Casslén
Departments of Obstetrics and Gynecology (T.S., B.C.) and Pathology
(A.E.), University Hospital, S-221 85 Lund, Sweden
Address all correspondence and requests for reprints to: Bertil Casslén, M.D., Ph.D., Department of Obstetrics and Gynecology, University Hospital, S-221 85 Lund, Sweden.
Endometrial angiogenesis is not well studied, but has potentialas a
model for studies of physiological angiogenesis. Migrationas well as
proliferation of vascular endothelial cells are modulatedby other
endometrial cells. This study analyzes the chemotacticsignal released
from endometrial tissue in a wound assay usinghuman microvascular
endothelial cells. Endometrial tissue explantsstimulate migration, and
this effect is significantly weakerwith explants taken at midcycle
than those obtained earlieror later in the cycle. Migration is
inhibited more than 50%by either blocking antibodies to the urokinase
plasminogen activatorreceptor (uPAR) or enzymatic removal of uPAR from
the cell surface.Also, migration is inhibited more than 50% by
antibodies toepidermal growth factor (EGF), but not by antibodies to
vascularendothelial growth factor or basic fibroblast growth factor.
Thecombination of anti-EGF and anti-uPAR antibodies does not further
reducethe response, suggesting that these antibodies target a common
pathway.Conditioned medium from endometrial explants contains EGF, and
EGFstimulates the migration of endothelial cells in a dose-dependent
way.This effect is completely blocked by antibodies to uPAR. These
datasuggest up-regulation of the uPA system by EGF. Conditionedmedium
from EGF-treated cells contains less uPA than mediumfrom control
cells. In contrast, binding of radiolabeled uPAreveals an increased
number of uPA-binding sites in EGF-treatedcells. Increased expression
of uPAR potentially increases theactivation and assembly of focal
adhesion sites, a prerequisitefor cell migration. We conclude that the
endometrial migratorysignal has two components. The major part of the
signal is blockedby antibodies to EGF, and the response is mediated
via up-regulationof uPAR in the endothelial cells. The other part of
the signalis unknown, and the response does not involve uPAR.
Decreasedendometrial chemotactic signal at midcycle is probably
relatedto decreased release of EGF, which is secondary to increased
bindingto endometrial cell membranes.
This article has been cited by other articles:
C. Print, R. Valtola, A. Evans, K. Lessan, S. Malik, and S. Smith Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome
Hum. Reprod.,
October 1, 2004;
19(10):
2356 - 2366.
[Abstract][Full Text][PDF]
D. Trisciuoglio, A. Iervolino, A. Candiloro, G. Fibbi, M. Fanciulli, U. Zangemeister-Wittke, G. Zupi, and D. Del Bufalo bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation: INVOLVEMENT OF ERK1/ERK2 ACTIVITY
J. Biol. Chem.,
February 20, 2004;
279(8):
6737 - 6745.
[Abstract][Full Text][PDF]
E. D. Albrecht, J. S. Babischkin, Y. Lidor, L. D. Anderson, L. C. Udoff, and G. J. Pepe Effect of estrogen on angiogenesis in co-cultures of human endometrial cells and microvascular endothelial cells
Hum. Reprod.,
October 1, 2003;
18(10):
2039 - 2047.
[Abstract][Full Text][PDF]
L. S. Gambino, N. G. Wreford, J. F. Bertram, P. Dockery, F. Lederman, and P. A.W. Rogers Angiogenesis occurs by vessel elongation in proliferative phase human endometrium
Hum. Reprod.,
May 1, 2002;
17(5):
1199 - 1206.
[Abstract][Full Text][PDF]
