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Transforming growth factor-ß1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways.
Ongali, Brice; Nicolakakis, Nektaria; Tong, Xin-Kang; Lecrux, Clotilde; Imboden, Hans; Hamel, Edith.
Affiliation
  • Ongali B; a Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Nicolakakis N; a Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Tong XK; a Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Lecrux C; a Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
  • Imboden H; b Institute of Cell Biology, University of Bern Baltzerstrasse 43012 Bern, Switzerland.
  • Hamel E; a Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada.
Can J Physiol Pharmacol ; 96(5): 527-534, 2018 May.
Article in En | MEDLINE | ID: mdl-29505736
Transgenic mice constitutively overexpressing the cytokine transforming growth factor-ß1 (TGF-ß1) (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-ß1 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-ß1-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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain / Signal Transduction / Receptor, Angiotensin, Type 1 / Transforming Growth Factor beta1 / Gliosis Limits: Animals Language: En Journal: Can J Physiol Pharmacol Year: 2018 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain / Signal Transduction / Receptor, Angiotensin, Type 1 / Transforming Growth Factor beta1 / Gliosis Limits: Animals Language: En Journal: Can J Physiol Pharmacol Year: 2018 Document type: Article Affiliation country: Country of publication: