Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.

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In this paper, we present evidence that activation of 5-hydroxytryptamine 2B (5-HT2B) receptors by serotonin (5-HT) leads to cell-cycle progression through retinoblastoma protein hyperphosphorylation and through activation of both cyclin D1͞cdk4 and cyclin E͞cdk2 kinases by a mechanism that depends on induction of cyclin D1 and cyclin E protein levels. The induction of cyclin D1 expression, but not that of cyclin E, is under mitogen-activated protein kinase (MAPK) control, indicating an independent regulation of these two cyclins in the 5-HT2B receptor mitogenesis. Moreover, by using the specific platelet-derived growth factor receptor (PDGFR) inhibitor AG 1296 or by overexpressing a kinasemutant PDGFR, we show that PDGFR kinase activity is essential for 5-HT2B-triggered MAPK͞cyclin D1, but not cyclin E, signaling pathways. 5-HT2B receptor activation also increases activity of the cyclins D1 and E ͉ G protein-coupled receptors ͉ platelet-derived growth factor receptor ͉ receptor signaling ͉ c-Src S erotonin (5-hydroxytryptamine, 5-HT) is involved in regulating cellular functions of central and peripheral nervous systems, endocrine and exocrine organs, as well as vascular and hematopoietic systems (1). These actions are mediated by numerous cognate receptors. For instance, 5-HT acts as a growth factor in a variety of cells, a function that is mediated by 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, or 5-HT2C receptor subtypes (2-5). The 5-HT2B receptor belongs to the G protein-coupled receptor (GPCR) family. Binding of 5-HT to 5-HT2B receptor activates G q protein, thereby stimulating phospholipase C, which initiates a rapid release of inositol trisphosphate and results in a rise in intracellular calcium levels (6). The signal transduction pathways activated downstream of the 5-HT2B receptor include the Ras and mitogen-activated protein kinase (MA PK of the MAPK͞ERK subfamily) pathways (3). Despite numerous studies of 5-HT signal transduction pathways, the critical steps from signal integration to its proliferative action have not been elucidated.The regulation of cell proliferation is a complex process controlled by external mitogenic factors. Once cells are induced to proliferate, passage through the mitotic cell cycle is directed by activation of a series of cyclins and their catalytic subunits, cyclin-dependent kinases (cdks) (7). Mitogenic factors act by stimulating both the proliferation of quiescent cells arrested in G 0 and the progression of the cell cycle through the restriction point in late G 1 . Progression through G 1 and the G 1 ͞S transition in mammalian cells is regulated by cdk4 and cdk6, which form complexes with cyclin D1, and by cdk2, which forms a complex with cyclin E (7). The G 1 cyclin͞cdk complexes drive the phosphorylation of retinoblastoma protein (pRb) that represents the limiting event in G 1 progression (8). However, the mechanism whereby 5-HT triggers G 1 progression has not been examined.The link between upstream signaling circuitry and the cellcycle machinery is of interest. Identified candid...