Fine Structural Modifications Of Heparan Sulfate Sulfation Patterns In Lung Are Associated With Functional Effects In Precapillary Pulmonary Hypertension

Sulfated glycosaminoglycans (GAG), heparan (HS) and chondroitin (CS) sulfates, are essential components of the extracellular matrix (ECM) in lung. In pulmonary hypertension (PH), altered ECM participates to lung arterial remodeling. We hypothesized that changes in GAG fine structure could alter their properties on growth factors and cell, thus leading to vascular remodeling in lung PH. Here we deciphered the fine structure and bioactivity of GAGs both in human and experimental PH, according to protocole approved by ethical committes. We performed quantitative (GAG total amount, HS/CS ratio), qualitative (disaccharidic sulfation pattern) and functional analysis (growth factor binding, cell proliferation) of HS and CS extracted from human lungs of patients with idiopathic (iPAH), heritable (hPAH) PAH, or pulmonary veno-occlusive disease (PVOD), and controls and of monocrotaline PH rats. Lungs of patients with iPAH, hPAH and PVOD, as well as Monocrotalin rats, revealed specific HS accumulation associated to selective HS disaccharides sulfation patterns. These changes were associated to significant functional modification of GAG binding affinity to growth factors (VEGF, FGF-2, PDGF), and significant induced cell proliferation in the presence of altered GAGs and growth factors. We suggest that changes of GAG composition and HS sulfation patterns in the lung could maintain a chronic inflammatory and vascular remodeling process leading to deregulated vascular cell proliferation through abnormal binding to growth factors. We propose to focus further on new glycanic targets in pathological lung for future therapeutic intervention.