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 [Go to this article.]

Figure 5
EP4 signaling is essential for ICF in the DA. (A) Developmental changes in ICF and HA production in rat DA. ICF was poor, with very little HA production at E19, whereas it became apparent with increased HA production at E21. At birth, the vascular lumen was filled by intimal cushion, and the DA was completely closed. DA intimal layers are also shown at higher magnification (middle row). HA production was visualized by by staining for HA-binding protein (HABP) (bottom row). Scale bars: 100 μm. (B) EP4/PKA stimuli promoted ICF in rat DA explants. ICF was fully developed and HABP -and Ki-67–positive staining was increased in DA explants in the presence of ONO-AE1-329 (10^–6 M) or by adenovirus-mediated PKA gene transfer (PKA adeno). ONO-AE1-329–mediated ICF was suppressed by adding H89 (10^–5 M). Arrows indicate the basement membrane of DA. (C) Wild-type (left) and EP4-KO (right) DA at birth. ICF of the vascular lumen was absent in neonatal EP4-KO DA. A marked reduction in HA production was found in EP4-KO DA, whereas a thick layer of HA deposit was present in wild-type DA.