Exacerbated VEGF up-regulation accompanies diabetes-aggravated hemorrhage in mice after experimental cerebral ischemia and delayed reperfusion  

作　　者：Angela Ka Wai Lai Tsz Chung Ng Victor Ka Lok Hung Ka Cheung Tam Chi Wai Cheung Sookja Kim Chung Amy Cheuk Yin Lo 

机构地区：[1]Department of Ophthalmology,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong Special Administration Region,China [2]Department of Anesthesiology,Laboratory and Clinical Research Institute for Pain,The University of Hong Kong,Hong Kong Special Administration Region,China [3]Macao University of Science and Technology,Taipa,Macao Special Administration Region,China,School of Biomedical Sciences,The State Key Laboratory of Pharmaceutical Biotechnology,The University of Hong Kong,Hong Kong Special Administration Region,China

出　　处：《Neural Regeneration Research》2022年第7期1566-1575,共10页中国神经再生研究（英文版）

基　　金：supported by Health and Medical Research Fund,the Food and Health Bureau,The Government of the Hong Kong Special Administrative Region(03142256);General Research Fund,Hong Kong Research Grants Council(GRF#HKU773613M);Seed Funding Programme for Basic Research(201811159123,201910159191);The University of Hong Kong(all to ACYL)。

摘　　要：Reperfusion therapy is the preferred treatment for ischemic stroke,but is hindered by its short treatment window,especially in patients with diabetes whose reperfusion after prolonged ischemia is often accompanied by exacerbated hemorrhage.The mechanisms underlying exacerbated hemorrhage are not fully understood.This study aimed to identify this mechanism by inducing prolonged 2-hour transient intraluminal middle cerebral artery occlusion in diabetic Ins2Akita/+mice to mimic patients with diabetes undergoing delayed mechanical thrombectomy.The results showed that at as early as 2 hours after reperfusion,Ins2Akita/+mice exhibited rapid development of neurological deficits,increased infarct and hemorrhagic transformation,together with exacerbated down-regulation of tight-junction protein ZO-1 and upregulation of blood-brain barrier-disrupting matrix metallopeptidase 2 and matrix metallopeptidase 9 when compared with normoglycemic Ins2+/+mice.This indicated that diabetes led to the rapid compromise of vessel integrity immediately after reperfusion,and consequently earlier death and further aggravation of hemorrhagic transformation 22 hours after reperfusion.This observation was associated with earlier and stronger up-regulation of pro-angiogenic vascular endothelial growth factor(VEGF)and its downstream phospho-Erk1/2 at 2 hours after reperfusion,which was suggestive of premature angiogenesis induced by early VEGF up-regulation,resulting in rapid vessel disintegration in diabetic stroke.Endoplasmic reticulum stress-related pro-apoptotic C/EBP homologous protein was overexpressed in challenged Ins2Akita/+mice,which suggests that the exacerbated VEGF up-regulation may be caused by overwhelming endoplasmic reticulum stress under diabetic conditions.In conclusion,the results mimicked complications in patients with diabetes undergoing delayed mechanical thrombectomy,and diabetes-induced accelerated VEGF up-regulation is likely to underlie exacerbated hemorrhagic transformation.Thus,suppression of the VEGF pathway could b

关 键 词：blood-brain barrier brain injury diabetes mellitus hemorrhagic transformation INFARCT ischemia/reperfusion injury middle cerebral artery occlusion mouse model stroke vascular endothelial growth factor 

分 类 号：R453[医药卫生—治疗学] R364[医药卫生—临床医学]