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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-05-1444.
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Blood, 1 December 2002, Vol. 100, No. 12, pp. 4040-4048
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Estrogen stimulates arachidonoylethanolamide release from human
endothelial cells and platelet activation
Mauro Maccarrone,
Monica Bari,
Natalia Battista, and
Alessandro Finazzi-Agrò
From the Department of Experimental Medicine and
Biochemical Sciences, University of Rome Tor Vergata,
Italy.
Estrogen replacement therapy has been associated with reduction of
cardiovascular events in postmenopausal women, though the mechanism for
this benefit remains unclear. Here we show that at physiological
concentrations estrogen activates the anandamide membrane transporter
of human endothelial cells and leads to rapid elevation of calcium
(apparent within 5 minutes) and release of nitric oxide (within 15 minutes). These effects are mediated by estrogen binding to a surface
receptor, which shows an apparent dissociation constant
(Kd) of 9.4 ± 1.4 nM, a maximum binding (Bmax) of 356 ± 12 fmol × mg
protein 1, and an apparent molecular mass of approximately
60 kDa. We also show that estrogen binding to surface receptors leads
to stimulation of the anandamide-synthesizing enzyme phospholipase D
and to inhibition of the anandamide-hydrolyzing enzyme fatty acid amide
hydrolase, the latter effect mediated by 15-lipoxygenase activity.
Because the endothelial transporter is shown to move anandamide across the cell membranes bidirectionally, taken together these data suggest
that the physiological activity of estrogen is to stimulate the
release, rather than the uptake, of anandamide from endothelial cells.
Moreover, we show that anandamide released from estrogen-stimulated endothelial cells, unlike estrogen itself, inhibits the secretion of
serotonin from adenosine diphosphate (ADP)-stimulated platelets. Therefore, it is suggested that the peripheral actions of anandamide could be part of the molecular events responsible for the beneficial effects of estrogen.
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