Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus arteriosus
J. Clin. Invest. Utako Yokoyama, et al. 116:3026 doi:10.1172/JCI28639 [
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Figure 3HA production is mediated by PGE/EP4/PKA signal in DA SMCs. (
A) HA production after 48-hour stimulation with agents. PGE
1, PGE
2, and ONO-AE1-329 at 10
–6 M dramatically increased HA production in the DA but not in the aorta. ONO-AE3-208 (10
–6 M), an EP4 antagonist, almost abolished the effect of PGE
1 (10
–6 M). The ONO-AE1-329–induced HA production was significantly attenuated by transfection with rat HAS2 siRNA (100 pmol) or H89. Forskolin (10
–5 M) and pCPT-cAMP (10
–4 M) significantly increased HA production in both the DA and aortic SMCs. Sulprostone (10
–6 M), an EP1/3-selective agonist, and butaprost (10
–6 M), an EP2-selective agonist, had little effect on HA secretion in DA SMCs. TGF-β (10 ng/ml) and PDGF-BB (10 ng/ml) significantly increased HA production in the aorta but not in the DA.
n = 4–8; **
P < 0.01,
#P < 0.001 compared with control.
†P < 0.05,
††P < 0.01,
ΧP < 0.001 compared with aorta. (
B) Dose-dependent HA production after 48-hour stimulation with ONO-AE1-329. (
C) Time-dependent HA production stimulated by 10
–6 M ONO-AE1-329.
n = 4; **
P < 0.01,
#P < 0.001 compared with control. ND, not done.
