Angiopoietin-1 and Angiopoietin-2 Expression Imbalance Influence in Early Period After Subarachnoid Hemorrhage
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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.
Abstract
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.
참고문헌 (21)
- Suarez JI, "Aneurysmal subarachnoid hemorrhage", N Engl J Med, 354, pp.387~396 (2006)
- Sehba FA, "The importance of early brain injury after subarachnoid hemorrhage", Prog Neurobiol, 97, pp.14~37 (2012)
- Ostrowski RP, "Molecular mechanisms of early brain injury after subarachnoid hemorrhage", Neurol Res, 28, pp.399~414 (2006)
- Pisapia JM, "Microthrombosis after experimental subarachnoid hemorrhage: time course and effect of red blood cell-bound thrombin-activated prourokinase and clazosentan", Exp Neurol, 233, pp.357~363 (2012)
- Song JN, "Dynamic change in cerebral microcirculation and focal cerebral metabolism in experimental subarachnoid hemorrhage in rabbits", Metab Brain Dis, 28, pp.33~43 (2013)
- Egashira Y, "White matter injury after subarachnoid hemorrhage: role of blood-brain barrier disruption and matrix metalloproteinase-9", Stroke, 46, pp.2909~2915 (2015)
- Augustin HG, "Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system", Nat Rev Mol Cell Biol, 10, pp.165~177 (2009)
- Brindle NP, "Signaling and functions of angiopoietin-1 in vascular protection", Circ Res, 98, pp.1014~1023 (2006)
- Daly C, "Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition", Cancer Res, 73, pp.108~118 (2013)
- Maisonpierre PC, "Angiopoietin-2, a natural antagonist for Tie2that disrupts in vivo angiogenesis", Science, 277, pp.55~60 (1997)
- Nourhaghighi N, "Altered expression of angiopoietins during blood-brain barrier breakdown and angiogenesis", Lab Invest, 83, pp.1211~1222 (2003)
- Siddiqui MR, "Angiopoietin-1 regulates brain endothelial permeability through PTPN-2 mediated tyrosine dephosphorylation of occludin", PLoS One, 10, pp.e0130857~ (2015)
- Fischer M, "Angiopoietin-1 is associated with cerebral vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage", BMC Neurol, 11, pp.59~ (2011)
- Bederson JB, "Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat", Stroke, 26, pp.1086~1091 (1995)
- Sugawara T, "A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model", J Neurosci Methods, 167, pp.327~334 (2008)
- Zhang BF, "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", Neurochem Res, 40, pp.591~599 (2015)
- Li Z, "Blood-brain barrier permeability change and regulation mechanism after subarachnoid hemorrhage", Metab Brain Dis, 30, pp.597~603 (2015)
- Liu L, "Vascular endothelial growth factor in brain edema formation after subarachnoid hemorrhage", Acta Neurochir Suppl, 121, pp.173~177 (2016)
- Hansen TM, "Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface", Cell Signal, 22, pp.527~532 (2010)
- Fagiani E, "Angiopoietins in angiogenesis", Cancer Lett, 328, pp.18~26 (2013)
- Lee JY, "Comparison of experimental rat models of early brain injury after subarachnoid hemorrhage", Neurosurgery, 65, pp.331~343 (2009)