Pengyu Pan1,2, Hengli Zhao1, Xuan Zhang1, Qiang Li1, Jie Qu1, Shilun Zuo1, Fan Yang3, Guobiao Liang2, John H Zhang4, Xin Liu1, Haiyang He5, Hua Feng6,7,8, Yujie Chen9,10. 1. Department of Neurosurgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China. 2. Department of Neurosurgery, General Hospital of Northern Theater Command (Shenyang Military Command), Shenyang, 110016, China. 3. Department of Pathophysiology and High-Altitude Pathology, College of High-Altitude Military Medicine, Third Military Medical University, Chongqing, 400038, China. 4. Neuroscience Research Center, Loma Linda University, Loma Linda, California, 92350, USA. 5. Institute of Immunology, Army Medical University (Third Military Medical University), Chongqing, 400038, China. 6. Department of Neurosurgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China. fenghua8888@vip.163.com. 7. State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, 400038, China. fenghua8888@vip.163.com. 8. Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Medical University, Chongqing, 400038, China. fenghua8888@vip.163.com. 9. Department of Neurosurgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China. yujiechen6886@foxmail.com. 10. Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Medical University, Chongqing, 400038, China. yujiechen6886@foxmail.com.
Abstract
OBJECTIVE: The potential roles and mechanisms of pericytes in maintaining blood-brain barrier (BBB) integrity, which would be helpful for the development of therapeutic strategies for subarachnoid hemorrhage (SAH), remain unclear. We sought to provide evidence on the potential role of pericytes in BBB disruption and possible involvement and mechanism of CypA signaling in both cultured pericytes and SAH models. METHODS: Three hundred fifty-three adult male C57B6J mice weighing 22 to 30 g, 29 CypA-/- mice, 30 CypA+/+ (flox/flox) mice, and 30 male neonatal C57B6J mice were used to investigate the time course of CypA expression in pericytes after SAH, the intrinsic function and mechanism of CypA in pericytes, and whether the known receptor CD147 mediates these effects. RESULTS: Our data demonstrated both intracellular CypA and CypA secretion increased after SAH and could activate CD147 receptor and downstream NF-κB pathway to induce MMP9 expression and proteolytic functions for degradation of endothelium tight junction proteins and basal membranes. CypA served as autocrine or paracrine ligand for its receptor, CD147. Although CypA could be endocytosed by pericytes, specific endocytosis inhibitor chlorpromazine did not have any effect on MMP9 activation. However, specific knockdown of CD147 could reverse the harmful effects of CypA expression in pericytes on the BBB integrity after SAH. CONCLUSIONS: This study demonstrated for the first time that CypA mediated the harmful effects of pericytes on BBB disruption after SAH, which potentially mediated by CD147/NF-κB/MMP9 signal, and junction protein degradation in the brain. By targeting CypA and pericytes, this study may provide new insights on the management of SAH patients.
OBJECTIVE: The potential roles and mechanisms of pericytes in maintaining blood-brain barrier (BBB) integrity, which would be helpful for the development of therapeutic strategies for subarachnoid hemorrhage (SAH), remain unclear. We sought to provide evidence on the potential role of pericytes in BBB disruption and possible involvement and mechanism of CypA signaling in both cultured pericytes and SAH models. METHODS: Three hundred fifty-three adult male C57B6J mice weighing 22 to 30 g, 29 CypA-/- mice, 30 CypA+/+ (flox/flox) mice, and 30 male neonatal C57B6J mice were used to investigate the time course of CypA expression in pericytes after SAH, the intrinsic function and mechanism of CypA in pericytes, and whether the known receptor CD147 mediates these effects. RESULTS: Our data demonstrated both intracellular CypA and CypA secretion increased after SAH and could activate CD147 receptor and downstream NF-κB pathway to induce MMP9 expression and proteolytic functions for degradation of endothelium tight junction proteins and basal membranes. CypA served as autocrine or paracrine ligand for its receptor, CD147. Although CypA could be endocytosed by pericytes, specific endocytosis inhibitor chlorpromazine did not have any effect on MMP9 activation. However, specific knockdown of CD147 could reverse the harmful effects of CypA expression in pericytes on the BBB integrity after SAH. CONCLUSIONS: This study demonstrated for the first time that CypA mediated the harmful effects of pericytes on BBB disruption after SAH, which potentially mediated by CD147/NF-κB/MMP9 signal, and junction protein degradation in the brain. By targeting CypA and pericytes, this study may provide new insights on the management of SAHpatients.