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

Abstract

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

Ischemia‐reperfusion injury of brain induces endothelial‐mesenchymal transition and vascular fibrosis via activating let‐7i/TGF‐βR1 double‐negative feedback loop

“…Overexpression of TGF‐β in astrocytes develops Alzheimer's like pathology by impairing the brain microvasculature and thickens the basement membrane, 52‐54 which suggests deposition of amyloid‐β peptide. A similar role of TGF‐β has also been confirmed after stroke 55 . Here we provided evidence that overexpression of let‐7i in ECs after stroke reduced collagen around vessel.…”

Antagonistic effects of IL-17 and Astragaloside IV on cortical neurogenesis and cognitive behavior after stroke in adult mice through Akt/GSK-3β pathway

“…Speaking of neurogenesis, it is inevitable to refer to GSK-3β, inhibition of which increases the proliferation of neural progenitors and promotes neurogenesis in some research 18 – 20 . Pro-differentiation factors such as Wnt and pro-proliferation factors secreted by astrocytes can also stimulate neurogenesis 21 . Therefore, whether IL-17 plays a negative role on neurogenesis by regulating cell proliferation and inflammation after stroke and the exact mechanism underlying is still not determined.…”

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…In addition, matrix adhesion by endothelial β1-integrin receptors affect claudin-5 expression and regulate BBB permeability (Osada et al, 2011). Interestingly, studies have also indicated the importance of the basement membrane in cerebrospinal fluid regulation (Morris et al, 2016;Albargothy et al, 2018;Howe et al, 2019). Impaired basement membrane integrity is a significant contributor to neuronal loss after stroke.…”

“…Aging is also an important factor in basement membrane integrity after stroke. TGF-β signaling in hypoxic astrocytes induces basement membrane fibrosis and chronically impairs perivascular CSF distribution, specifically in aged animals after permanent MCAo (Howe et al, 2019), providing a new mechanism by which brain injury can lead to prolonged functional impairment in the elderly.…”

“…-Leakage of blood-borne factors into brain parenchyma results in rapid microglia activation that enwrap and phagocytose ECs in the peri-infarct region. Chow et al, 2001;Hangai et al, 2002;Beck et al, 2008;Krum et al, 2008;Yu et al, 2010;Yenari et al, 2010;Jiao et al, 2011;Ben-Zvi et al, 2014;ElAli et al, 2014;Knowland et al, 2014;Jolivel et al, 2015;Choi et al, 2016;Nahirney et al, 2016;Thomsen et al, 2017;Underly et al, 2017;Eldahshan et al, 2019;Howe et al, 2019;Munji et al, 2019;Yao, 2019;Shibahara et al, 2020. Hemorrhagic stroke -ECs proliferate around hematoma following ICH.…”