Evidence for the Fucoidan/P-Selectin Axis as a Therapeutic Target in Hypoxia-induced Pulmonary Hypertension.

Abstract

<b>Rationale:</b> Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Fucoidan, a polysaccharidic ligand of the adhesion molecule P-selectin, exhibits antiproliferative properties. The effects of the fucoidan/P-selectin axis on vascular remodeling and pulmonary hypertension (PH) after hypoxia remain unexplored. <b>Objectives:</b> We aimed to evaluate the therapeutic potential of targeting the fucoidan/P-selectin axis in PH. <b>Methods:</b> Mice with PH induced by chronic hypoxia (35 d) were given either fucoidan (from <i>Fucus vesiculosus</i>) 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. <b>Measurements and Main Results:</b> Fucoidan attenuated chronic hypoxia-induced PH in mice, reducing pulmonary vascular remodeling and restoring RV function. <i>In vitro</i>, fucoidan inhibited hypoxia and growth factor-stimulated PASMC proliferation and migration. Chronic hypoxia caused an upregulation of P-selectin in the medial layer of the small pulmonary arteries. P-selectin was persistently upregulated in PASMCs of human and hypoxia-induced experimental PH. HIF-1α (hypoxia-inducible factor 1α) directly bound to the P-selectin promoter and transcriptionally activated P-selectin in hypoxia. P-selectin blockage resulted in a marked reduction of PASMC proliferation <i>in vitro</i>. Blockage of P-selectin by administration of anti-P-selectin Rb40.34 antibody and P-selectin-deficient mice improved vascular remodeling and restored RV function. <b>Conclusions:</b> Fucoidan is a potent natural adjuvant that represents a promising therapeutic approach for PH. Our data indicate a previously unrecognized role of P-selectin in the proliferative response of PASMCs associated with PH.