Human Prostaglandin Transporter Gene ( hPGT ) is Regulated by Fluid Mechanical Stimuli in Cultured Endothelial Cells and Expressed in Vascular Endothelium in Vivo

Abstract

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 1␤ cytokines (rhIL-1␤) 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. (Circulation. 1998;98:2396-2403.)

Prostaglandin transporter PGT is expressed in cell types that synthesize and release prostanoids

“…Topper et al (34) reported that antisera against the COOH terminus of human PGT labeled endothelia, but not other structures, in the human kidney, results which vary from the present data. In addition to recognizing PGT in endothelia, our anti-rat mAb20 also recognizes immunoreactivity in glomerular mesangial cells, arteriolar muscularis layers, collecting ducts, medullary interstitial cells, and papillary surface epithelia.…”

KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium

“…The reported increased PGI2 bioavailability in response to flow might very well be accomplished by the highly increased expression of the KLF2-induced prostaglandin transporter SLCO2A1, which itself was previously shown to be highly responsive to shear stress. 36 Collectively, the presented data lead to the novel insight that KLF2 gene regulation is almost entirely dedicated to the control of many of the genes that define the key functions of the normal functioning endothelium of the completely developed healthy arterial tree. The large number of downstream transcriptional targets of KLF2 (Table 2) precludes a simple direct transcription factor-to-function relation.…”

Expression of genes controlling transport and catabolism of prostaglandin E2in lipopolysaccharide fever

“…One study showed that PGE 2 transport was inhibited in the rabbit uvea by topical application of LPS (2), whereas another study failed to detect any effect of IL-1␤ on PGT expression in human endothelial cells in vitro (64). Administration of IL-1␤ or TNF-␣ in vitro (37,46) and shock-inducing doses of LPS in vivo (6,23,39) were shown to inhibit the catabolism of PGE 1 and PGE 2 and expression of 15-PGDH.…”