Evidence for Fucoidan-P-selectin Axis as a Therapeutic Target on Hypoxia-induced Pulmonary Hypertension.
Am J Respir Crit Care Med. 2018 Dec 17. Epub 2018 Dec 17. PMID: 30557519
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.