Yae Hu1,2, Ruhong Yan1, Ce Zhang1, Zhichao Zhou1,3, Meng Liu1, Can Wang1, Hong Zhang4, Liang Dong1, Tiantian Zhou1, Yi Wu1, Ningzheng Dong5,6,3, Qingyu Wu5,6,7. 1. From the Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Medical College, Soochow University, Suzhou, China (Y.H., R.Y., C.Z., Z.Z., M.L., C.W., L.D., T.Z., Y.W., N.D., Q.W.). 2. Department of Pathophysiology, Medical School of Nantong University, China (Y.H.). 3. MOH Key Laboratory of Thrombosis and Hemostasis, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China (Z.Z., N.D.). 4. Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Soochow University, Suzhou, China (H.Z.). 5. From the Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Medical College, Soochow University, Suzhou, China (Y.H., R.Y., C.Z., Z.Z., M.L., C.W., L.D., T.Z., Y.W., N.D., Q.W.) wuq@ccf.org ningzhengdong@suda.edu.cn. 6. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, China (N.D., Q.W.). 7. Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, OH (Q.W.).
Abstract
OBJECTIVE: Thrombophilia is a major complication in preeclampsia, a disease associated with placental hypoxia and trophoblast inflammation. Preeclampsia women are known to have increased circulating microparticles that are procoagulant, but the underlying mechanisms remain unclear. In this study, we sought to understand the mechanism connecting placental hypoxia, circulating microparticles, and thrombophilia. APPROACH AND RESULTS: We analyzed protein markers on plasma microparticles from preeclampsia women and found that the increased circulating microparticles were mostly from endothelial cells. In proteomic studies, we identified HMGB1 (high-mobility group box 1), a proinflammatory protein, as a key factor from hypoxic trophoblasts in stimulating microparticle production in human umbilical vein endothelial cells. Immunodepletion or inhibition of HMGB1 in the conditioned medium from hypoxic human trophoblasts abolished the endothelial microparticle-stimulating activity. Conversely, recombinant HMGB1 stimulated microparticle production in cultured human umbilical vein endothelial cells. The microparticles from recombinant HMGB1-stimulated human umbilical vein endothelial cells promoted blood coagulation and neutrophil activation in vitro. Injection of recombinant HMGB1 in pregnant mice increased plasma endothelial microparticles and promoted blood coagulation. In preeclampsia women, elevated placental HMGB1 expression was detected and high levels of plasma HMGB1 correlated with increased plasma endothelial microparticles. CONCLUSIONS: Our results indicate that placental hypoxia-induced HMGB1 expression and release from trophoblasts are important mechanism underlying increased circulating endothelial microparticles and thrombophilia in preeclampsia.
OBJECTIVE:Thrombophilia is a major complication in preeclampsia, a disease associated with placental hypoxia and trophoblast inflammation. Preeclampsiawomen are known to have increased circulating microparticles that are procoagulant, but the underlying mechanisms remain unclear. In this study, we sought to understand the mechanism connecting placental hypoxia, circulating microparticles, and thrombophilia. APPROACH AND RESULTS: We analyzed protein markers on plasma microparticles from preeclampsiawomen and found that the increased circulating microparticles were mostly from endothelial cells. In proteomic studies, we identified HMGB1 (high-mobility group box 1), a proinflammatory protein, as a key factor from hypoxic trophoblasts in stimulating microparticle production in human umbilical vein endothelial cells. Immunodepletion or inhibition of HMGB1 in the conditioned medium from hypoxichuman trophoblasts abolished the endothelial microparticle-stimulating activity. Conversely, recombinant HMGB1 stimulated microparticle production in cultured human umbilical vein endothelial cells. The microparticles from recombinant HMGB1-stimulated human umbilical vein endothelial cells promoted blood coagulation and neutrophil activation in vitro. Injection of recombinant HMGB1 in pregnant mice increased plasma endothelial microparticles and promoted blood coagulation. In preeclampsiawomen, elevated placental HMGB1 expression was detected and high levels of plasma HMGB1 correlated with increased plasma endothelial microparticles. CONCLUSIONS: Our results indicate that placental hypoxia-induced HMGB1 expression and release from trophoblasts are important mechanism underlying increased circulating endothelial microparticles and thrombophilia in preeclampsia.
Authors: Roberta Palumbo; Maurilio Sampaolesi; Francesco De Marchis; Rossana Tonlorenzi; Sara Colombetti; Anna Mondino; Giulio Cossu; Marco E Bianchi Journal: J Cell Biol Date: 2004-01-26 Impact factor: 10.539
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2019-12-23 Impact factor: 8.311