Circulating fibrocytes in pulmonary vascular remodelling

Abstract

Einleitung: Circulating fibrocytes (CFs) comprise a recently described new cell type of blood born derived fibroblast like cells that are recruited from the circulation to sites of wound repair, vascular remodelling or fibrotic tissue remodelling. A role of these cells in the pulmonary vascular remodelling in pulmonary hypertension has been proposed. Hence, we focussed on these cells type to decipher their role in pulmonary hypertension. Methoden: FACS, confocal laser scanning microscopy; Western blot, qPCR, Rap pull down assay and in vivo hypoxia induced pulmonary hypertension murine model. Ergebnisse: We observed that freshly isolated human peripheral mononuclear cells (PBMCs) upon treatment with treprostinil exhibited poor cell adhesion and subsequently reduction of cell differentiation in ex-vivo expansion. Our further investigations indicated a cAMP induced integrin impairment that was a PKA independent process transduced via an alternative cAMP-RAP-ERK axis. We created blood chimeric animals by bone marrow transplantation of wild type C57 mice with bone marrow derived from eGFP mice. We found a significant contribution of these cells to pulmonary vascular remodelling of the chronic hypoxic mouse and this cellular recruitment was inhibited upon treatment with continuous treprostinil infusion in the mouse directed by an implanted minipump. Diskussion: We could show that prostanoids, which are approved for clinical therapy of pulmonary hypertension, potently inhibit the in vitro differentiation of CF from blood as well as the in vivo recruitment and integration into pulmonary resistance arteries. We thereby showed that CFs are a new therapeutic target in this devastating disease. The further aims are now to more precisely dissect the pathway of prostanoids action on circulating fibrocytes by introducing mutated Rap, Raf and ERK proteins.