Effects of the prostanoids on the proliferation or hypertrophy of cultured murine aortic smooth muscle cells

Effects of the prostanoids on the growth of cultured aortic vascular smooth muscle cells (VSMCs) were examined using mice lacking prostanoid receptors. Proliferation of VSMCs was assessed by measuring [3H]-thymidine incorporation and the cell number, and their hypertrophy by [14C]-leucine incorporation and protein content. In VSMCs from wild-type mice, expressions of mRNAs for the EP4 and TP were most abundant, followed by those for the IP, EP3 and FP, when examined by competitive reverse transcriptase-PCR. Those for the EP1, EP2 and DP, however, could not be detected. AE1-329, an EP4 agonist, and cicaprost, an IP agonist, inhibited platelet derived growth factor (PDGF)-induced proliferation of VSMCs from wild-type mice; these inhibitory effects disappeared completely in VSMCs from EP4−/− and IP−/− mice, respectively. In accordance with these effects, AE1-329 and cicaprost stimulated cAMP production in VSMCs from wild-type mice, which were absent in VSMCs from EP4−/− and IP−/− mice, respectively. Effects of PGE2 on cell proliferation and adenylate cyclase were almost similar with those of AE1-329 in VSMCs from wild-type mice, which disappeared in VSMCs from EP4−/− mice. PGD2 inhibited PDGF-induced proliferation of VSMCs from both wild-type and DP−/− mice to a similar extent. This action of PGD2 was also observed in VSMCs from EP4−/− and IP−/− mice. In VSMCs from wild-type mice, I-BOP, a TP agonist, showed potentiation of PDGF-induced hypertrophy. I-BOP failed to show this action in VSMCs from TP−/− mice. The specific agonists for the EP1, EP2 or EP3, and PGF2α showed little effect on the growth of VSMCs. These results show that PGE2, PGI2 and TXA2 modulate PDGF-induced proliferation or hypertrophy of VSMCs via the EP4, IP and TP, respectively, and that the inhibitory effect of PGD2 on PDGF-induced proliferation is not mediated by the DP, EP4 or IP. British Journal of Pharmacology (2002) 136, 530–539; doi:10.1038/sj.bjp.0704749