Apelin-13 protects neurovascular unit against ischemic injuries through the effects of vascular endothelial growth factor |
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| Affiliation: | 1. Department of Neurology, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, No. 600 Yishan Road, Shanghai 200030, China;2. Department of Otolaryngology, Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, Beijing 102218, China;3. School of Medicine, Tsinghua University, No. 30 Shuangqing Road, Haidian District, Beijing 100084, China;4. Department of Neurosurgery, Tsinghua University Yuquan Hospital, No. 5 Shijingshan Road, Shijingshan District, Beijing 100049, China;5. Department of Neurology, Huashan Hospital, Fudan University, No. 12 Mid. Wulumuqi Road, Shanghai 200040, China;1. Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan;2. Department of Neurology, Iwate National Hospital, 48 Dorota Yamashita, Yamanome, Ichinoseki, Iwate 021-0056, Japan;3. Department of Neurology, South Miyagi Medical Center, 38-1 Ogawara-machi-nishi, Shibata-gun, Miyagi 989-1253, Japan;4. Department of Internal Medicine, South Miyagi Medical Center, 38-1 Ogawara-machi-nishi, Shibata-gun, Miyagi 989-1253, Japan;1. Division of Cardiology, Emory University School of Medicine, Atlanta, GA, United States;2. Division of Pulmonary Medicine, Emory University School of Medicine, Atlanta, GA, United States;3. Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, United States;4. Department of Dermatology, Atlanta VA Medical Center and Emory University School of Medicine, Atlanta, GA, United States;5. Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States;1. Department of Physiology, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China;2. Department of Gastroenterology, First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, China |
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| Abstract: | Apelin-13 has protective effects on many neurological diseases, including cerebral ischemia. Here, we aimed to test Apelin-13's effects on ischemic neurovascular unit (NVU) injuries and investigate whether the effects were dependent on vascular endothelial growth factor (VEGF). We detected the expression of VEGF and its receptors (VEGFRs) induced by Apelin-13 injection at 1 d, 3 d, 7 d and 14 d after middle cerebral artery occlusion (MCAO). Meanwhile, we examined the effects of Apelin-13 on NVU in both in vivo and in vitro experiments as well as whether the effects were VEGF dependent by using VEGF antibody. We also assessed the related signal transduction pathways via multiple inhibitors. We demonstrated Apelin-13 highly increased VEGF and VEGFR-2 expression, not VEGFR-1. Importantly, Apelin-13 led to neurological functions improvement by associating with promotion of angiogenesis as well as reduction of neuronal death and astrocyte activation, which was markedly blocked by VEGF antibody. In cell cultures, Apelin-13 protected neurons, astrocytes and endothelial cells against oxygen-glucose deprivation (OGD) injuries. Moreover, the effect of Apelin-13 to up-regulate VEGF was suppressed by extracellular signal-regulated kinase (ERK) inhibitor U0126 and phosphatidylinositol 3′-kinase (PI3K) inhibitor LY294002. Our data suggest protective effects of Apelin-13 on ischemic NVU injuries are highly associated with the increase of VEGF binding to VEGFR-2, possibly acting through activation of ERK and PI3K/Akt pathways. |
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