Based on these in silico results, we selectively focused on let-7b to study its cellular function relevant to the disease, because the predicted targets of it were likely to be involved in CTEPH pathogenesis. Let-7b has been reported to be an antioncogenic miRNA which is frequently lost in many tumors. By the preliminary correlation analysis with clinical characteristics of CTEPH patients, we found that circulating let-7b levels were decreased in patients with negative AVR, which was generally regarded to be related with serious pulmonary WZ8040 vascular remodeling. This illuminating result indicated the possible role of let-7b in pulmonary vascular biology of CTEPH pathogenesis. In the further mechanism study, we found that let-7b could target ET-1 and TGFBR1, which have been reported to be closely related to the pathogenesis of CTEPH. Antagonizing let-7b could up-regulate ET-1 and TGFBR1 expression, which promoted PAECs and PASMCs migration. These effects would lead to persistent constriction or remodeling of pulmonary vascular bed and promote CTEPH development. Positive correlation was also found between let-7b and PAI-1 or D-Dimer, which were regarded to be elevated in thrombotic diseases. Therefore, the positive correlation gave no direct indication for the role of let-7b in coagulation process of CTEPH. The exact mechanism still needs further study. It was mainly secreted by endothelial cells and mediate vascular constriction and PASMCs proliferation through endothelin A and B receptors. In CTEPH patients, increases of ET-1 were significantly correlated with clinical characteristics. In addition, elevated serum ET-1 was demonstrated to be a predictor of bad pulmonary endarterectomy outcome. Endothelin receptor antagonists have emerged as cornerstone treatment for PAH for more than 10 years. In CTEPH patients, especially inoperable ones, ETAs were also of benefit in hemodynamics. ET-1 expression was a complex biological process. In the present study, we showed a new aspect of ET-1 expression regulation at the posttranscriptional level by a miRNA. The down-regulation of let-7b was correlated with elevation of plasma ET-1 level, and this might be accomplished through two ways. First, ET-1 was a direct target of let-7b, and it was derepressed when let-7b was down-regulated. Second, TGF-b was one of the most potent regulators of ET-1 expression. It strongly increased ET-1 mRNA and protein expression in endothelial, and specifically, TGF-b induced ET-1 expression preferentially through the TGFBR1/Smad3 pathway. Our results suggested that decreased let-7b up-regulated the expression of TGFBR1, which was in turn possibly involved in the elevation of ET-1 in CTEPH patients. In addition, ET-1 is a mitogenic growth factor especially in pulmonary circulation. By wound healing assay, we further illustrated that derepression of ET1 by let-7b partially participated in the PAECs migration, and the elevated ET-1 could induce PASMCs migration. The aberrant migration of PAECs and PASMCs was further related to the pulmonary vascular remodeling of CTEPH patients. Besides regulation of ET-1 expression, TGFBR1 and downstream signals played an important role in biology of pulmonary vessels.