(Circulation. 1998;98:2396-2403.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Human Prostaglandin Transporter Gene (hPGT) is Regulated by Fluid Mechanical Stimuli in Cultured Endothelial Cells and Expressed in Vascular Endothelium in Vivo
From the Vascular Research Division (J.N.T., G.S., K.R.A., M.A.G.), the Department of Pathology (B.A.S., F.J.S.), and the Cardiovascular Division (J.N.T.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; and from Millennium Pharmaceuticals Inc, Cambridge, Mass (J.C., E.A.W., D.F.). Dr Topper is now in the Cardiovascular Division, Department of Medicine, Stanford University School of Medicine, Stanford, Calif.
Correspondence to James N. Topper MD, PhD, Cardiovascular Division, Department of Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail jtopper{at}leland.stanford.edu
Background—biomechanical forces generated by blood flow within the cardiovascular system have been proposed as important modulators of regional endothelial phenotype and function. This process is thought to involve the regulation of vascular gene expression by physiological fluid mechanical stimuli such as fluid shear stresses.
Methods and Results—We demonstrate sustained upregulation of a
recently identified gene encoding a human prostaglandin
transporter (hPGT) in cultured human vascular
endothelium exposed to a
physiological fluid mechanical stimulus in vitro.
This biomechanical induction is selective in that steady laminar shear
stress is sufficient to upregulate the hPGT gene at the
level of transcriptional activation, whereas a comparable level of
turbulent shear stress (a nonphysiological
stimulus) is not. Various biochemical stimuli, such as bacterial
endotoxin and the inflammatory cytokines recombinant human interleukin
1ß cytokines (rhIL-1ß) and tumor necrosis factor-
(TNF-), did not significantly induce hPGT. Using a
specific antiserum to hPGT, we demonstrate endothelial
expression within the arterial vasculature and the
microcirculation of highly vascularized tissues such as the heart.
Conclusions—Our results identify hPGT as an inducible gene in vascular endothelium and suggest that biomechanical stimuli generated by blood flow in vivo may be important determinants of hPGT expression. Furthermore, this demonstration of regulated endothelial expression of hPGT implicates this molecule in the regional metabolism of prostanoids within the cardiovascular system.
Key Words: prostaglandins • cardiovascular system • stress • endothelium • gene expression • carrier proteins
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