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Editorial
. 2021 Jun 15;203(12):1455-1458.
doi: 10.1164/rccm.202101-0007ED.

NEDD9, a Hypoxia-upregulated Mediator for Pathogenic Platelet-Endothelial Cell Interaction in Pulmonary Hypertension

Jian Wang  1   2 , Kai Yang  2 , Jason X-J Yuan  1
Affiliations
Editorial

NEDD9, a Hypoxia-upregulated Mediator for Pathogenic Platelet-Endothelial Cell Interaction in Pulmonary Hypertension

Jian Wang et al. Am J Respir Crit Care Med. .
No abstract available

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Figures

Figure 1.
Figure 1.
Proposed mechanisms showing the pathogenic role of NEDD9 in hypoxia-induced platelet activation and platelet–endothelial cell (EC) interaction and their relationship to the development of pulmonary vascular remodeling. Hypoxia, together with hemodynamic shear stress and inflammation, activates platelets by inducing Ca2+ influx through Piezo1 (a mechanosensitive Ca2+ channel) and TRPC6 (a receptor-operated Ca2+ channel) and increasing cytosolic [Ca2+]cyt in platelets. Hypoxia upregulates NEDD9 in lung vascular ECs via HIF-1α, and NEDD9 binds to P-selectin on the surface membrane of activated platelets, resulting in platelet–EC adhesion. Synthesis and release thromboxane A2 (TXA2) and ADP from activated platelets further enhance the hypoxia- and inflammation-mediated activation of platelets. NEDD9 can also enhance platelet–smooth muscle cell interaction via exosomes released from EC and cause pulmonary vascular fibrosis. NEDD9 can also upregulate collagen III via NKX2-5 and COL3A1 and cause obliterative intimal lesions in the small arteries and arterioles. NEDD9 can also up-regulate the collagen III gene (COL3A1) expression via NKX2-5 (homeobox protein NKX2-5), increase collagen deposition in extracellular matrix (and plasma), and cause obliterative intimal lesions in the small arteries and arterioles. Blocking NEDD9 with specific antibodies such as msAb-N9-P2 disrupts NEDD9/P-selectin interaction, inhibits platelet–EC adhesion, and attenuates pulmonary vascular remodeling and fibrosis. α2β1 = α2β1 integrin; αIIbβ3 = platelet αIIbβ3 integrin; Ab-P-Sel = antibody against P-selectin; Ab-PSGL-1 = antibody against P-selectin glycoprotein ligand-1; GPIbα = platelet glycoprotein Ib α chain; GPIb–IX–V = glycoprotein Ib–IX–V receptor complex; GPVI = platelet glycoprotein VI (collagen receptor); ICAM-1 = intercellular adhesion molecule 1; IP3R = inositol trisphosphate receptor; P2X1 = P2X purinergic receptor 1; PSGL-1 = P-selectin glycoprotein ligand-1; TRPC6 = transient receptor potential canonical 6 channel; VWF = von Willebrand factor.
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Comment on

  • NEDD9 Is a Novel and Modifiable Mediator of Platelet-Endothelial Adhesion in the Pulmonary Circulation.
    Alba GA, Samokhin AO, Wang RS, Zhang YY, Wertheim BM, Arons E, Greenfield EA, Lundberg Slingsby MH, Ceglowski JR, Haley KJ, Bowman FP, Yu YR, Haney JC, Eng G, Mitchell RN, Sheets A, Vargas SO, Seo S, Channick RN, Leary PJ, Rajagopal S, Loscalzo J, Battinelli EM, Maron BA. Alba GA, et al. Am J Respir Crit Care Med. 2021 Jun 15;203(12):1533-1545. doi: 10.1164/rccm.202003-0719OC. Am J Respir Crit Care Med. 2021. PMID: 33523764 Free PMC article.

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