Evidence for Fucoidan-P-selectin Axis as a Therapeutic Target on Hypoxia-induced Pulmonary Hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Fucoidan, polysacharidic ligand of an adhesion molecule P-selectin exhibits anti-proliferative properties. The effects of Fucoidan/P-selectin axis on vascular remodeling and pulmonary hypertension (PH) following hypoxia remain unexplored. Objectives: We aimed to evaluate the therapeutic potential of targeting the fucoidan/P-selectin axis in PH. Methods: Mice with PH induced by chronic hypoxia (35 days) were given either fucoidan (from Fucus vesiculosus) or anti-P-selectin antibody (Rb40.34) during days 21–35. Right ventricular (RV) function was determined by echocardiography. Vascular morphometry was assessed by immunohistochemistry. Human and experimental PH lungs and PASMCs were used for assessment of P-selectin expression and function. Measurements and Main Results: Fucoidan attenuated chronic hypoxia-induced PH in mice, reducing pulmonary vascular remodelling and restoring RV function. In vitro, fucoidan inhibited hypoxia and growth factor stimulated PASMC proliferation and migration. Chronic hypoxia caused an up-regulation of P-selectin in the medial layer of small pulmonary arteries. P- selectin is persistently upregulated in PASMCs of human and hypoxia-induced experimental PH. HIF-1α directly bound to P-selectin promoter, transcriptionally activated P-selectin in hypoxia. P-selectin blockage resulted in a marked reduction of PASMCs proliferation in vitro. Blockage of P-selectin by administration of anti-P- selectin Rb40.34 antibody and P-selectin deficient mice improved vascular remodelling and restored RV function. Conclusions: Fucoidan is a potent natural adjuvant representing a promising therapeutic approach for PH. Our data indicate a previously unrecognized role of P-selectin in proliferative response of PASMCs associated with PH.