Fibrocytes comprise a recently described cell type of blood-derived, 
fibroblast-like cells that are recruited from the circulation to sites of wound 
repair, vascular remodeling, or fibrotic tissue remodeling. We recently showed 
that the stable prostacyclin analogue treprostinil, a clinically approved drug 
for pulmonary arterial hypertension (PAH), significantly reduced the recruitment 
of fibrocytes to sites of vascular remodeling in experimental hypoxic pulmonary 
hypertension. Here we report on the molecular mechanism underlying the 
inhibitory action of treprostinil on the adhesion and differentiation of human 
fibrocytes. Human fibrocytes expressed the prostanoid receptors, prostaglandin I 
(IP) receptors and prostaglandin E subtype receptors (EP2 and EP4). The 
generation of intracellular cyclic adenosine monophosphate (cAMP) by 
treprostinil reduced the expression of the integrins CD49 and CD29 when freshly 
isolated human peripheral blood mononuclear cells were treated with 
treprostinil. Cell-matrix adhesion was significantly impaired by treatment with 
treprostinil. We present evidence for a treprostinil/cAMP-induced downstream 
suppression of extracellular regulated kinase (ERK) that is transmitted via a 
protein kinase A-independent pathway through Rap proteins, which sequester Ras. 
The resulting dephosphorylated state of c-Raf limits the activity of ERK. The 
cell-matrix adhesion assay with the ERK inhibitor further confirmed that the 
adhesion of fibrocytes was impaired. Thus our data suggest that treprostinil 
inhibits the adhesion and differentiation of fibrocytes by limiting the activity 
of ERK via the cAMP-Rap axis.