• Tatyana Novoyatleva, Baktybek Kojonazarov, Andreas Owczarek, Swathi Veeroju, Nabham Rai, Ingrid Henneke, Mario Böhm, Friedrich Grimminger, Hossein A Ghofrani, Werner Seeger, Norbert Weissmann, and Ralph T Schermuly.
• 1 Universities of Giessen and Marburg Lung Center, Department of Internal Medicine, Member of the German Center for Lung Research, Justus Liebig University Giessen, Giessen, Germany; and.
• Am. J. Respir. Crit. Care Med. 2019 Jun 1; 199 (11): 140714201407-1420.

AbstractRationale: 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. 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 d) 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 remodeling and restoring RV function. In vitro, 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 in vitro. 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. Conclusions: 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.

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