Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). (RVH) pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls c-kit mutant mice had decreased RVSP RVH pulmonary vascular remodeling and proliferation. Consistent with these findings administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP RVH pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. Introduction Neonatal chronic hypoxia-induced pulmonary hypertension (PH) is characterized by vascular pruning and profound remodeling of peripheral pulmonary vessels (1). These pulmonary vascular changes mimic those seen in infants with severe bronchopulmonary dysplasia and are a significant cause of morbidity and mortality. Currently mechanistic pathways remain unclear and there are few efficacious therapies. CD117 or c-kit a tyrosine kinase receptor encoded at the W/Kit locus (2) is mainly utilized as a stem cell marker (3 4 Yet this receptor is also expressed on myocardial tissue mast cells dendritic cells systemic vascular smooth muscle cells epithelial cells and fetal pulmonary vascular endothelial cells (2 5 The ligand for c-kit is stem cell factor (SCF). Encoded at the steel locus on murine chromosome 10 SCF is expressed by several cells including endothelial cells and lung Pramipexole dihydrochloride monohyrate fibroblasts (8). Interestingly although recent studies have demonstrated increased c-kitpos cells in the media and adventitia of remodeled pulmonary arterioles the role of SCF/c-kit signaling in the pathogenesis of PH is unclear (9–11). It is however known that binding of SCF to c-kit results in dimerization of the receptor with subsequent activation of its intrinsic tyrosine kinase and phosphorylation of its tyrosine residues (12). These phosphorylated sites are known to function as docking stations for several signal transduction proteins which induce the activation of signaling pathways believed to be responsible for SCF/c-kit role in cell differentiation survival and proliferation (13 14 This latter process is particularly relevant Pramipexole dihydrochloride monohyrate in the context of PH as Pramipexole dihydrochloride monohyrate pulmonary vascular proliferation is one of the main mechanisms postulated to contribute to the pulmonary vascular remodeling evidenced in this disease. Consistent with this theory other investigators have suggested that c-kit and SCF play important roles in systemic vascular remodeling. The expression of c-kit and SCF were increased in atherosclerotic vessels (5) and mice with defective c-kit signaling (c-kit mutant mice) had decreased systemic vascular remodeling following injury (14 15 Moreover administration of imatinib mesylate (a non-specific c-kit antagonist) improved pulmonary vascular resistance as well as walking distance in idiopathic PH (16). This present study sought to test the hypothesis that activation of c-kit signaling potentiates neonatal chronic hypoxia-induced pulmonary vascular remodeling by increasing pulmonary vascular cell proliferation. Using a chronic hypoxia in vivo model of neonatal PH we show that neonatal hypoxic c-kit mutant mice exhibit decreased PH right ventricular hypertrophy (RVH) pulmonary vascular cell proliferation and remodeling as compared to control hypoxic mice. In addition CCR5 we show that antagonism of c-kit attenuated neonatal chronic hypoxia-induced pulmonary vascular proliferation and remodeling. Further questioning to ascertain the mechanisms by which c-kit may participate in chronic hypoxia-induced pulmonary vascular remodeling revealed that SCF/c-kit signaling increased neonatal pulmonary vascular smooth muscle cell proliferation by augmenting extracellular signal-regulated protein kinase (ERK) 1/2 activation. These findings provide important insight into the involvement of SCF/ c-kit signaling in the pathogenesis of Pramipexole dihydrochloride monohyrate PH. Results SCF and c-kit expression in remodeled pulmonary arterioles of mice with PH We first sought to ascertain.