© 1998 American Heart Association, Inc.
Original Contributions |
Urokinase Receptor-Dependent Upregulation of Smooth Muscle Cell Adhesion to Vitronectin by Urokinase
From the University of Pennsylvania School of Medicine, Philadelphia (A.W.C., A.K., E.S.B.); Centocor, Inc (E.S.B.), Malvern, Pa; and the Division of Cardiology, Department of Medicine, Georgetown University, Washington, DC (S.S.O.).
Correspondence to S. Steve Okada, Division of Cardiology, Building D, Room 396B, Georgetown University Medical Center, 4000 Reservoir Rd NW, Washington, DC 20007-2197. E-mail okadas{at}medlib.georgetown.edu
Abstract—The
plasminogen activator system has been
implicated in the modulation of the response to vascular injury.
Although urokinase-type plasminogen activator
(uPA) and its receptor (uPAR) may enhance matrix degradation as well as
migration and invasion by smooth muscle cells (SMCs), their roles in
cell adhesion are uncertain. Therefore, we examined the ability of uPA
and uPAR to modulate adhesion of cultured human vascular SMCs to
various matrices. We demonstrated a dose-dependent stimulation of
adhesion by single-chain uPA (scuPA) to vitronectin
(maximum 1.55-fold [±0.04-fold] increase, 10 nmol/L,
P<0.002) but not to laminin, collagen I, or collagen
IV. Baseline adhesion to vitronectin was completely
inhibited by both EDTA and RGD peptide but was restored to >40% of
control in the presence of scuPA (P=0.001 and 0.046,
respectively). Adhesion to vitronectin was also
significantly enhanced by the amino-terminal fragment of uPA
(P=0.007) and two-chain, high-molecular-weight uPA
(P<0.01) but not by the low-molecular-weight fragment
of uPA, which lacks the receptor-binding domain. Aprotinin, a plasmin
inhibitor, had no effect on baseline or scuPA-stimulated
adhesion, suggesting a plasmin-independent process. Preincubation of
scuPA with soluble uPAR inhibited scuPA stimulation of adhesion by
88±14% (P=0.01), as did pretreatment of SMCs with
phosphatidylinositol-specific phospholipase C, which removes
glycophosphatidylinositol-anchored proteins, including uPAR. Antibodies
to both 
vß3 and
vß5 integrin inhibited baseline adhesion
but not scuPA stimulation. Finally, coating plates with scuPA alone
enabled cell adhesion, which could be inhibited by both soluble uPAR
and anti-uPAR antibodies. These data suggest that uPA stimulates
adhesion of SMCs specifically to vitronectin and that it is
mediated by an interaction with uPAR. Upregulation of both proteins
after vascular injury may facilitate migration through stimulation of
both matrix degradation and cell adhesion.
Key Words: smooth muscle cell adhesion • upregulation • urokinase • vitronectin • urokinase receptor
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