Changes in the balance of phosphoinositide 3-kinase/protein kinase B (Akt)and the mitogen-activated protein kinases (ERK/p38MAPK) determine a phenotype of visceral and vascular smooth muscle cells

The molecular mechanisms behind phenotypic modulation of smooth muscle cell s (SMCs) remain unclear. In our recent paper, we reported the establishment of novel culture system of gizzard SMCs (Hayashi, K., H. Saga, Y. Chimori, K, Kimura, Y. Yamanaka, and K, Sobue, 1998. J, Biol, Chem. 273: 28860-2886 7), in which insulin-like growth factor-I (IGF-I) was the most potent for m aintaining the differentiated SIMC phenotype, and IGF-I triggered the phosp hoinositide 3-kinase (PU-K) and protein kinase B (PKB(Akt)) pathway. Here, we investigated the signaling pathways involved in de-differentiation of gi zzard SMCs induced by PDGF-BB, bFGF and EGF In contrast to the IGF-I-trigge red pathway, PDGF-BB, bFGF, and EGF coordinately activated ERK and p38MAPK pathways, Further, the forced expression of active forms of MEK1 and MKK6, which are the up-stream kinases of ERK and p38MAPK, respectively, induced d e-differentiation even when SMCs were stimulated with IGF-I, Among three gr owth factors, PDGF-BB only triggered the PI3-K/PKB(Akt) pathway in addition to the ERK and p38MAPK pathways. When the ERK and p38MAPK pathways were si multaneously blocked by their specific inhibitors or an active form of eith er PI3-K or PKB(Akt) was transfected, PDGF-BB in turn initiated to maintain the differentiated SMC phenotype, We applied these findings to vascular SM Cs, and demonstrated the possibility that the same signaling pathways might be involved in regulating the vascular SMC phenotype, These results sugges t that changes in the balance between the PI3-K/PKB(Akt) pathway and the ER K and p38MAPK pathways would determine phenotypes of visceral and vascular SMCs, We further reported that SMCs cotransfected with active forms of MEK1 and MKK6 secreted a nondialyzable, heat-labile protein factor(s) which ind uced de-differentiation of surrounding normal SMCs.