Objective: Platelet-derived growth factor-BB activates platelet- derived growth factor receptor-β and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-mus- cle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. e390 www.ccmjournal.org June 2016 • Volume 44 • Number 6 Objective: Platelet-derived growth factor-BB activates plateletderived growth factor receptor-β and promotes vascular smooth muscle cell phenotypic transformation. Elevated levels of non-muscle myosin IIB (SMemb) are found in secretory smooth muscle cells along with inflammatory mediators, such as intercellular adhesion molecule-1, which can amplify neutrophil infiltration into the brain. In the present study, we investigated the role of platelet-derived growth factor-BB/platelet-derived growth factor receptor-β following intracerebral hemorrhage–induced brain injury in mice, with emphasis on its ability to promote vascular smooth muscle cell phenotypic transformation followed by increased intercellular adhesion molecule-1 expression and elevated neutrophil infiltration in the vicinity of the hematoma. We also determined the extent to which plasmin from the hematoma influences the platelet-derived growth factor-BB/platelet-derived growth factor receptor-β system subsequent to intracerebral hemorrhage. Design: Controlled in vivo laboratory study. Setting: Animal research laboratory. Subjects: One hundred and fifty six eight-week-old male CD1 mice. Interventions: Brain injury was induced by autologous arterial blood or plasmin injection into mouse brains. Small interfering RNA targeting platelet-derived growth factor receptor-β was administered 24 hours before intracerebral hemorrhage. A platelet-derived growth factor receptor antagonist, Gleevec, was administered following intracerebral hemorrhage. A mitogenactivated protein kinase–activated protein kinase 2 inhibitor (KKKALNRQLGVAA) was delivered with platelet-derived growth factor-BB in naïve animals. Platelet-derived growth factor-BB was injected with a plasmin inhibitor (ε-aminocaproic acid) in intracerebral hemorrhage mice. Plasmin-injected mice were given plateletderived growth factor receptor-β small interfering RNA 24 hours before the operation. Neurological deficits, brain edema, western blots, and immunofluorescence were evaluated. Measurements and Main Results: Platelet-derived growth factor receptor-β small interfering RNA attenuated SMemb and intercellular adhesion molecule-1 expression and neutrophil infiltration at 24 hours post injury and reduced neurological deficits and brain edema at 24 and 72 hours following intracerebral hemorrhage. The platelet-derived growth factor receptor antagonist, Gleevec, reduced SMemb and intercellular adhesion molecule-1 expression. Platelet-derived growth factor receptor-β activation led to increased expression of intercellular adhesion molecule-1 and was Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000001425 1Department of Emergency Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China. 2Departments of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA. 3Department of Neurosurgery, the First Affiliated Hospital of Soochow University, Suzhou, China. 4Department of Pharmacy, the First Affiliated Hospital of Soochow University, Suzhou, China. 5Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China. 6Department of Neurosurgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China. 7Department of Psychology, Loma Linda University, Loma Linda, CA. 8Department of Pediatrics, Loma Linda University, Loma Linda, CA. 9Department of Anesthesiology, Loma Linda University, Loma Linda, CA. 10Department of Neurosurgery, Loma Linda University, Loma Linda, CA. Drs. Yang and Wu contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ ccmjournal). Drs. Yang, Wu, Miao, Yang Zhang, Obenaus, Tang, and Xu received support for article research from the National Institutes of Health (NIH). Dr. Manaenko disclosed work for hire. Dr. Pearce disclosed that all support was grant related from the NIH and received support for article research from the NIH. His institution received funding from the National Institutes of Health: National Institute of Neurological Disorders and Stroke. Dr. John H. Zhang received support for article research from the NIH P01 NS082184-01. His institution received funding from the NIH. Dr. Hartman disclosed that he does not have any potential conflicts of interest. For information regarding this article, E-mail: sz_xf@suda.edu.cn Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice