Angiopoietin-1 and Angiopoietin-2 Expression Imbalance Influence in Early Period After Subarachnoid Hemorrhage

Purpose Microvascular endothelial integrity is important for maintaining the blood-brain barrier (BBB). However, subarachnoid hemorrhage (SAH) disrupts this integrity, making the BBB dysfunctional—an important pathophysiological change after SAH. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) regulate microvascular permeability by balancing each other’s expression. Methods This study investigated the dynamics of Ang-1 and Ang-2 expression after SAH and the protective effect of Ang-1 on BBB functioning using an endovascular puncture model of rat SAH. The Ang-1 and Ang-2 expression in brain tissue was determined by immunohistochemistry. In addition, Western blotting was used to estimate Ang-1 and Ang-2 concentration and to compare them at 6–72 hours post-SAH cortex and hippocampus. Evans blue viability assay was used to evaluate BBB permeability, and neurological testing was implemented to evaluate neurological impairment during SAH. Results It was found that following SAH, Ang-1 expression decreases and Ang-2 expression increases in the cortex, hippocampus, and microvessels. The Ang-1/Ang-2 ratio decreased as quickly as 6 hours after SAH and reached its lowest 1 day after SAH. Finally, it was found that exogenous Ang-1 reduces SAH-associated BBB leakage and improves neurological function in post-SAH rats. Conclusions Our findings suggest that the equilibrium between Ang-1 and Ang-2 is broken in a period shortly after SAH, and the treatment of exogenous Ang-1 injection alleviates neurological dysfunctions through decreasing BBB destruction.

[1]  R. Keep,et al.  White Matter Injury After Subarachnoid Hemorrhage: Role of Blood–Brain Barrier Disruption and Matrix Metalloproteinase-9 , 2015, Stroke.

[2]  K. Kim,et al.  Angiopoietin-1 Regulates Brain Endothelial Permeability through PTPN-2 Mediated Tyrosine Dephosphorylation of Occludin , 2015, PloS one.

[3]  Yunhui Liu,et al.  Blood–brain barrier permeability change and regulation mechanism after subarachnoid hemorrhage , 2015, Metabolic Brain Disease.

[4]  Y. Li,et al.  Etanercept Alleviates Early Brain Injury Following Experimental Subarachnoid Hemorrhage and the Possible Role of Tumor Necrosis Factor-α and c-Jun N-Terminal Kinase Pathway , 2015, Neurochemical Research.

[5]  Ming Zhang,et al.  Dynamic change in cerebral microcirculation and focal cerebral metabolism in experimental subarachnoid hemorrhage in rabbits , 2013, Metabolic Brain Disease.

[6]  John H. Zhang,et al.  The importance of early brain injury after subarachnoid hemorrhage , 2012, Progress in Neurobiology.

[7]  S. Stein,et al.  Microthrombosis after experimental subarachnoid hemorrhage: Time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan , 2012, Experimental Neurology.

[8]  R. Helbok,et al.  Angiopoietin-1 is associated with cerebral vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage , 2011, BMC neurology.

[9]  T. Tahir,et al.  Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface , 2010, Cellular signalling.

[10]  R. Keep,et al.  COMPARISON OF EXPERIMENTAL RAT MODELS OF EARLY BRAIN INJURY AFTER SUBARACHNOID HEMORRHAGE , 2009, Neurosurgery.

[11]  Gavin Thurston,et al.  Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system , 2009, Nature Reviews Molecular Cell Biology.

[12]  John H. Zhang,et al.  A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model , 2008, Journal of Neuroscience Methods.

[13]  R. Ostrowski,et al.  Molecular mechanisms of early brain injury after subarachnoid hemorrhage , 2006, Neurological research.

[14]  K. Alitalo,et al.  Signaling and Functions of Angiopoietin-1 in Vascular Protection , 2006, Circulation research.

[15]  D. Stewart,et al.  Altered Expression of Angiopoietins During Blood-Brain Barrier Breakdown and Angiogenesis , 2003, Laboratory Investigation.

[16]  Thomas N. Sato,et al.  Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. , 1997, Science.

[17]  J. Bederson,et al.  Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. , 1995, Stroke.

[18]  E. Macdonald,et al.  Aneurysmal Subarachnoid Hemorrhage , 1989, The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses.

[19]  Lei Liu,et al.  Vascular Endothelial Growth Factor in Brain Edema Formation After Subarachnoid Hemorrhage. , 2016, Acta neurochirurgica. Supplement.

[20]  G. Christofori,et al.  Angiopoietins in angiogenesis. , 2013, Cancer letters.

[21]  Alastair H Kyle,et al.  Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. , 2013, Cancer research.