Transforming growth factor-β promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke.

Autor: Howe MD; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., Furr JW; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., Munshi Y; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., Roy-O'Reilly MA; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., Maniskas ME; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., Koellhoffer EC; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., d'Aigle J; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., Sansing LH; Department of Neurology, Yale University School of Medicine, 1450 Chapel Street, New Haven, CT, 06511, USA., McCullough LD; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA., Urayama A; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St., Houston, TX, 77030, USA. Akihiko.Urayama@uth.tmc.edu.
Jazyk: angličtina
Zdroj: GeroScience [Geroscience] 2019 Oct; Vol. 41 (5), pp. 543-559. Date of Electronic Publication: 2019 Nov 13.
DOI: 10.1007/s11357-019-00118-7
Abstrakt: Aging and stroke alter the composition of the basement membrane and reduce the perivascular distribution of cerebrospinal fluid and solutes, which may contribute to poor functional recovery in elderly patients. Following stroke, TGF-β induces astrocyte activation and subsequent glial scar development. This is dysregulated with aging and could lead to chronic, detrimental changes within the basement membrane. We hypothesized that TGF-β induces basement membrane fibrosis after stroke, leading to impaired perivascular CSF distribution and poor functional recovery in aged animals. We found that CSF entered the aged brain along perivascular tracts; this process was reduced by experimental stroke and was rescued by TGF-β receptor inhibition. Brain fibronectin levels increased with experimental stroke, which was reversed with inhibitor treatment. Exogenous TGF-β stimulation increased fibronectin expression, both in vivo and in primary cultured astrocytes. Oxygen-glucose deprivation of cultured astrocytes induced multiple changes in genes related to astrocyte activation and extracellular matrix production. Finally, in stroke patients, we found that serum TGF-β levels correlated with poorer functional outcomes, suggesting that serum levels may act as a biomarker for functional recovery. These results support a potential new treatment strategy to enhance recovery in elderly stroke patients.
Databáze: MEDLINE
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