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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Transforming growth factor -beta 1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways
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Transforming growth factor -beta 1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways

机译:转化生长因子-Beta 1通过血管紧张素II型1受体介导的信号通路诱导脑血管功能障碍和星分激

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Transgenic mice constitutively overexpressing the cytokine transforming growth factor-beta 1 (TGF-beta 1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-beta 1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-beta 1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.
机译:组成患有细胞因子转化生长因子-β1(TGF-β1)(TGF小鼠)(TGF小鼠)的转基因小鼠显示脑血管改变,如阿尔茨海默病(AD)和血管认知障碍和痴呆(VCID),但没有或只是微妙的认知缺陷。 TGF-β1可以通过与血管紧张素II(Angii)类型1受体(AT1R)信号传导途径的相互作用来施加其有害效果的一部分。通过测量脑血管反应性,血管纤维化,一氧化氮合酶活性,十分球症和MIGE的蛋白质标记水平,用AT1R阻滞剂洛​​萨沙顿(6个月)(10 Mg / kg每天)或血管紧张素转化酶抑制剂烯丙醇(每天3mg / kg)。两种治疗方法恢复了对乙酰胆碱,降钙素基因相关肽,内皮素-1的严重受损的脑血管反应性,以及在老年的TGF小鼠中的一氧化氮的基线可用性。氯沙坦,但不是Enalapril,显着降低了星形症和脑血管血管水平的粒状蛋白质结缔组织生长因子,同时提高了抗纤维酶基质组金属肽酶-9的水平。记忆不受老化和治疗的影响。结果表明,通过AT1R介导机制,TGF-β1诱导的脑血管功能障碍和神经炎症的神经炎炎症的枢转作用。此外,他们表明Angii阻滞剂可以适用于与AD和VCID相关的血管病变和星形症。

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