TY - JOUR TI - NEDD9 is a Novel and Modifiable Mediator of Platelet-Endothelial Adhesion in the Pulmonary Circulation AU - Alba, George A. AU - Samokhin, Andriy O. AU - Wang, Rui-Sheng AU - Zhang, Ying-Yi AU - Wertheim, Bradley M. AU - Arons, Elena AU - Greenfield, Edward A. AU - Lundberg Slingsby, Martina H. AU - Ceglowski, Julia R. AU - Haley, Kathleen J. AU - Bowman, Frederick P. AU - Yu, Yen-Rei AU - Haney, John C AU - Eng, George AU - Mitchell, Richard N. AU - Sheets, Anthony AU - Vargas, Sara O. AU - Seo, Sachiko AU - Channick, Richard N. AU - Leary, Peter J AU - Rajagopal, Sudarshan AU - Loscalzo, Joseph AU - Battinelli, Elisabeth M. AU - Maron, Bradley A T2 - American Journal of Respiratory and Critical Care Medicine AB - Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications. Objectives: Identify a hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling. Methods and Measurements: Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody to inhibit platelet-endothelial adhesion, which was tested in cells from chronic thromboembolic pulmonary hypertension (CTEPH) patients and three animal models in vivo. Results: The protein NEDD9 was identified in the hypoxia-thrombosome network in silico. Compared to normoxia, hypoxia (0.2% O2) for 24 hr increased hypoxia inducible factor-1α-dependent NEDD9 upregulation in vitro. Increased NEDD9 was localized to the plasma membrane surface of cells from controls and CTEPH patients. In endarterectomy specimens, NEDD9 co-localized with the platelet surface adhesion molecule P-Selectin. Our custom-made anti-NEDD9 antibody targeted the NEDD9-P-Selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from controls in vitro and CTEPH patients ex vivo. Compared to controls, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by adenosine diphosphate were decreased in NEDD9-/- mice or wild type mice treated with the anti-NEDD9 antibody, which also decreased chronic pulmonary thromboembolic remodeling in vivo. Conclusions: InThe NEDD9-P-Selectin protein-protein interaction is a modifiable target by which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH. DA - 2021/02/01/ PY - 2021 DO - 10.1164/rccm.202003-0719OC DP - atsjournals.org (Atypon) J2 - Am J Respir Crit Care Med SN - 1073-449X UR - https://www.atsjournals.org/doi/10.1164/rccm.202003-0719OC Y2 - 2021/02/03/17:15:48 ER -