The Roles of TGF-β Signaling in Cerebrovascular Diseases

Zhang, Yizhe; Yang, Xiao

doi:10.3389/fcell.2020.567682

Cited by 28 publications

(25 citation statements)

References 158 publications

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“…Further, previous studies showed that TGFβ1 mRNA and that of its induced pro-fibrotic target genes is upregulated in Dutch-type CAA and is associated with increased CAA severity (Moursel et al, 2018;Zhang & Yang, 2020). TGFβ1 has been reported to induce vascular fibrosis, mediate brain endothelial dysfunction, increased BBB permeability through downstream molecules such as FSP1 (S100A4) and Vim, and is associated with perivascular accumulation of ApoE (Moursel et al, 2018;Derada Troletti et al 2016;Derada Troletti et al 2019;Ueberham et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Distinct brain regional proteome changes in the rTg‐DI rat model of cerebral amyloid angiopathy

Schrader

Nostrand

2021

Journal of Neurochemistry

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calcium binding protein A4; S100A6, S100 calcium binding protein A6; SVD, small vessel disease; SWATH-MS, Sequential Window Acquisition of all Theoretical Mass Spectra-MS; Syt2, synaptotagmin-2; TGF-β1, transforming growth factor β1; TNFα, tumor necrosis factor α; TOF-MS, time of flight MS; TPA, total protein approach; UPLC, ultra performance liquid chromatography; VCID, vascular cognitive impairment and dementia; Vim, vimentin; XIC, extracted ion current chromatogram.

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Section: Discussionmentioning

confidence: 99%

Distinct brain regional proteome changes in the rTg‐DI rat model of cerebral amyloid angiopathy

Schrader

Nostrand

2021

Journal of Neurochemistry

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“…Activation of TGF-β1 was predicted in the cortex of rTg-DI and rTg-DI/SHR-SP rats ( Figure 12A ). We have previously shown increases in TGF-β1 mRNA expression and IPA indicated activation of TGF-β1 in 12 M rTg-DI rats, and other studies have linked upregulation of TGF-β1 mRNA in Dutch-type CAA to increased CAA severity ( Moursel et al, 2018 ; Zhang and Yang, 2020 ; Zhu et al, 2020 ; Schrader et al, 2021 ). Interestingly, it has been reported that TGF-β1 deficiency in the neurovascular unit increases BBB permeability and that TGF-β1 released from astrocytes promotes BBB integrity ( Garcia et al, 2004 ; Derada Troletti et al, 2016 ).…”

Section: Discussionmentioning

confidence: 72%

Impact of Non-pharmacological Chronic Hypertension on a Transgenic Rat Model of Cerebral Amyloid Angiopathy

et al. 2022

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Cerebral amyloid angiopathy (CAA), a common comorbidity of Alzheimer’s disease (AD), is a cerebral small vessel disease (CSVD) characterized by deposition of fibrillar amyloid β (Aβ) in blood vessels of the brain and promotes neuroinflammation and vascular cognitive impairment and dementia (VCID). Hypertension, a prominent non-amyloidal CSVD, has been found to increase risk of dementia, but clinical data regarding its effects in CAA patients is controversial. To understand the effects of hypertension on CAA, we bred rTg-DI transgenic rats, a model of CAA, with spontaneously hypertensive, stroke prone (SHR-SP) rats producing bigenic rTg-DI/SHR-SP and non-transgenic SHR-SP littermates. At 7 months (M) of age, cohorts of both rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic blood pressures. However, transgene human amyloid β-protein (Aβ) precursor and Aβ peptide levels, as well as behavioral testing showed no changes between bigenic rTg-DI/SHR-SP and rTg-DI rats. Subsequent cohorts of rats were aged further to 10 M where bigenic rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic and diastolic blood pressures. Vascular amyloid load in hippocampus and thalamus was significantly decreased, whereas pial surface vessel amyloid increased, in bigenic rTg-DI/SHR-SP rats compared to rTg-DI rats suggesting a redistribution of vascular amyloid in bigenic animals. There was activation of both astrocytes and microglia in rTg-DI rats and bigenic rTg-DI/SHR-SP rats not observed in SHR-SP rats indicating that glial activation was likely in response to the presence of vascular amyloid. Thalamic microbleeds were present in both rTg-DI rats and bigenic rTg-DI/SHR-SP rats. Although the number of thalamic small vessel occlusions were not different between rTg-DI and bigenic rTg-DI/SHR-SP rats, a significant difference in occlusion size and distribution in the thalamus was found. Proteomic analysis of cortical tissue indicated that bigenic rTg-DI/SHR-SP rats largely adopt features of the rTg-DI rats with enhancement of certain changes. Our findings indicate that at 10 M of age non-pharmacological hypertension in rTg-DI rats causes a redistribution of vascular amyloid and significantly alters the size and distribution of thalamic occluded vessels. In addition, our findings indicate that bigenic rTg-DI/SHR-SP rats provide a non-pharmacological model to further study hypertension and CAA as co-morbidities for CSVD and VCID.

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“…Interestingly, experiments on HUVECs demonstrated that shear stress activates TGF-β, leading to downstream activation of Krüppel-Like Factor 2 (KLF2) and eNOS in an ALK5 dependent manner ( Walshe et al, 2013 ; Figure 2 ). Moreover, TGF-β malfunction through the SMAD signaling pathway has been linked to diverse cerebrovascular diseases related to aberrant endothelial cell proliferation (including HHT), as reviewed by Zhang and Yang (2020) .…”

Section: Mechanisms Of Vessel Enlargementmentioning

confidence: 99%

Vessel Enlargement in Development and Pathophysiology

Gifre-Renom

Jones

2021

Front. Physiol.

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From developmental stages until adulthood, the circulatory system remodels in response to changes in blood flow in order to maintain vascular homeostasis. Remodeling processes can be driven by de novo formation of vessels or angiogenesis, and by the restructuration of already existing vessels, such as vessel enlargement and regression. Notably, vessel enlargement can occur as fast as in few hours in response to changes in flow and pressure. The high plasticity and responsiveness of blood vessels rely on endothelial cells. Changes within the bloodstream, such as increasing shear stress in a narrowing vessel or lowering blood flow in redundant vessels, are sensed by endothelial cells and activate downstream signaling cascades, promoting behavioral changes in the involved cells. This way, endothelial cells can reorganize themselves to restore normal circulation levels within the vessel. However, the dysregulation of such processes can entail severe pathological circumstances with disturbances affecting diverse organs, such as human hereditary telangiectasias. There are different pathways through which endothelial cells react to promote vessel enlargement and mechanisms may differ depending on whether remodeling occurs in the adult or in developmental models. Understanding the molecular mechanisms involved in the fast-adapting processes governing vessel enlargement can open the door to a new set of therapeutical approaches to be applied in occlusive vascular diseases. Therefore, we have outlined here the latest advances in the study of vessel enlargement in physiology and pathology, with a special insight in the pathways involved in its regulation.

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The Roles of TGF-β Signaling in Cerebrovascular Diseases

Cited by 28 publications

References 158 publications

Distinct brain regional proteome changes in the rTg‐DI rat model of cerebral amyloid angiopathy

Distinct brain regional proteome changes in the rTg‐DI rat model of cerebral amyloid angiopathy

Impact of Non-pharmacological Chronic Hypertension on a Transgenic Rat Model of Cerebral Amyloid Angiopathy

Vessel Enlargement in Development and Pathophysiology

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