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Platelet/Endothelial Cell Adhesion Molecule-1 Serves as a
Costimulatory Agonist Receptor That Modulates Integrin-Dependent
Adhesion and Aggregation of Human Platelets
David Varon,
Denise E. Jackson,
Boris Shenkman,
Rima Dardik,
Ilya Tamarin,
Naphtali Savion, and
Peter J. Newman
From The National Hemophilia Center and the Institute of Thrombosis
and Hemostasis, Tel-Hashomer, Israel; the Blood Research Institute, The
Blood Center of Southeastern Wisconsin, Milwaukee, WI; The Goldschleger
Eye Research Institute, Tel-Aviv University, Tel-Aviv, Israel; and the
Departments of Cellular Biology and Pharmacology, Medical College of
Wisconsin, Milwaukee, WI.
Platelet/endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kD
member of the Ig gene superfamily that is expressed on the surface of
circulating platelets, monocytes, neutrophils, and selective T-cell
subsets. It is also a major component of the endothelial cell
intercellular junction. Previous studies have shown that cross-linking
PECAM-1 on the surface of leukocytes results in the activation of
adhesion molecules of both the  1 and 2
integrin family. In addition, the process of leukocyte transendothelial
migration appears to be mediated, at least in part, by homophilic
adhesive interactions that take place between leukocyte and endothelial
cell junctional PECAM-1 molecules. However, little is known about the
functional role of this membrane glycoprotein in human platelets. In
the present study, we examined the effects of PECAM-1 engagement on
integrin-mediated platelet-extracellular matrix or platelet-platelet
interactions. Bivalent, but not monovalent, anti-PECAM-1 monoclonal
antibodies (MoAbs) specific for membrane-proximal Ig-homology domain 6 significantly augmented platelet deposition (increased surface
coverage) and aggregation (increased average size) onto extracellular
matrix, under both oscillatory or defined low shear flow conditions
(200 s 1) in a modified cone and plate viscometer.
Moreover, bivalent anti-domain 6 MoAbs were capable of serving as
costimulatory agonists to markedly enhance both adenosine diphosphate
(ADP)- and platelet activating factor (PAF)-induced platelet
aggregation responses. These antibodies appeared to act via outside-in
signal transduction through PECAM-1, as evidenced by the fact that
their binding (1) led to conformational changes in the
 IIb3 integrin complex, (2) induced
surface expression of P-selectin, and (3) resulted in the tyrosine
phosphorylation of PECAM-1. Together, these data support a role for
PECAM-1 in cellular activation and suggest that PECAM-1 may serve as a
costimulatory agonist receptor capable of modulating integrin function
in human platelets during adhesion and aggregation.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 500-507
© 1998 by The American Society of Hematology.
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