Lung heparan and chondroitine sulfate imbalance, and functional changes in pulmonary hypertension

Background In pulmonary arterial hypertension (PAH) endothelial cell dysfunction, smooth muscle cell (SMC) proliferation and altered extracellular matrix (ECM) participate to lung arterial remodeling. Sulfated glycosaminoglycans (GAGs) such as heparan sulfate (HS) and chondroitin sulfate (CS) are essential components of the ECM in lung development. Working hypothesis HS and CS control cell migration and proliferation through selective binding of chemokines and growth factors. We hypothesized that changes in GAG pattern in PAH lung could participate to vascular remodeling. Methods We performed quantitative (HS/CS ratio, total amount), and functional analysis (growth factor binding, cell proliferation) of HS and CS extracted from lungs of PAH patients and controls, and of monocrotaline PH rats Results Lungs of HTAPi, HTAPh and MVO patients, revealed specific patterns of HS/CS accumulation and imbalance. GAG interaction with growth factors, modulation of SMC proliferation and expression of GAG biosynthetic enzymes are in progress. PH rats showed a 2.5 fold increase of GAGs/mg lung, preceding vascular remodeling and due to HS increase at day1 followed by CS at day7. These changes were correlated to significant functional modifications of GAG binding to growth factors (VEGF, FGF-2). Conclusions Changes of GAG composition in PAH lung could lead to deregulated vascular cell proliferation and maintain a chronic inflammatory and vascular remodeling process.