Elevated TGFβ signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome

Branyan, Kayla W.; Labelle‐Dumais, Cassandre; Wang, Xiaowei; Hayashi, Genki; Lee, Bryson; Peltz, Zoe; Gorman, Seán; Li, Bo Qiao; Mao, Mao; Gould, Douglas B.

doi:10.1016/j.matbio.2022.11.007

Cited by 7 publications

(7 citation statements)

References 129 publications

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“…1 D). Furthermore, consistent with our previous findings, 33 , 34 expression of Serpine1 , a major TGFβ target gene, was elevated in anterior segments from Col4a1 +/G1344D mice compared to Col4a1 +/+ mice, and we showed that Tgfbr2 heterozygosity reduced Serpine1 levels ( Fig. 1 E).…”

Section: Resultssupporting

confidence: 93%

TGFβ Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage

Mao,

Kuo,

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose Mutations in the genes encoding type IV collagen alpha 1 (COL4A1) and alpha 2 (COL4A2) cause a multisystem disorder that includes ocular anterior segment dysgenesis (ASD) and glaucoma. We previously showed that transforming growth factor beta (TGFβ) signaling was elevated in developing anterior segments from Col4a1 mutant mice and that reducing TGFβ signaling ameliorated ASD, supporting a role for the TGFβ pathway in disease pathogenesis. Here, we tested whether altered TGFβ signaling also contributes to glaucoma-related phenotypes in Col4a1 mutant mice. Methods To test the role of TGFβ signaling in glaucoma-relevant phenotypes, we genetically reduced TGFβ signaling using mice with mutated Tgfbr2 , which encodes the common receptor for all TGFβ ligands in Col4a1 +/G1344D mice. We performed slit-lamp biomicroscopy and optical coherence tomography for qualitative and quantitative analyses of anterior and posterior ocular segments, histological analyses of ocular tissues and optic nerves, and intraocular pressure assessments using rebound tonometry. Results Col4a1 +/G1344D mice showed defects of the ocular drainage structures, including iridocorneal adhesions, and phenotypes consistent with glaucomatous neurodegeneration, including thinning of the nerve fiber layer, retinal ganglion cell loss, optic nerve head excavation, and optic nerve degeneration. We found that reducing TGFβ receptor 2 (TGFBR2) was protective for ASD, ameliorated ocular drainage structure defects, and protected against glaucomatous neurodegeneration in Col4a1 +/G1344D mice. Conclusions Our results suggest that elevated TGFβ signaling contributes to glaucomatous neurodegeneration in Col4a1 mutant mice.

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Section: Resultssupporting

confidence: 93%

TGFβ Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage

Mao,

Kuo,

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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“…Elevated TGF-β signaling has been recently described in Col4a1 mutant mice. Genetic knockdown of TGF-β ligand and blocking TGF-β signaling using neutralizing antibodies or pharmacological inhibitors improved ocular and cerebrovascular pathogenesis associated with Col4a1 mutations 32,56,57 . Activation of TGF-β receptors can stimulate PI3K activity through a non-canonical signaling pathway involving the TRAF6 ubiquitin ligase 58,59 , suggesting that enhanced TGF-β signaling contributes to PIP 2 insufficiency in Col4a1 +/G394V mice.…”

Section: Discussionmentioning

confidence: 99%

PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease

Thakore

Yamasaki

Ali

et al. 2023

Preprint

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Neurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report a Col4a1 mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) in brain capillary endothelial cells, leading to the loss of inwardly rectifier K+ (Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP2 by converting it to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of aged Col4a1 mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD.

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“…Interestingly, a recent study suggested that age-related arterial SMC loss might be attributable to a decline in NOTCH3 signaling ( 66 ). The cerebroretinal vasculature of Col4a1 -mutant mice expressing heterozygous missense mutations that substitute critical glycine residues (G498V, G1064D, or G1344D) within the triple helical domain of COL4A1 also exhibits arterial SMC loss ( 65 , 67 , 68 ). Patients and mice with COL4A1 glycine-altering variants develop spontaneous ICHs in deep brain regions; importantly, pathological analyses of mutant mice indicate that ICHs originate from arteries with reduced SMC coverage, and demonstrate a strong correlation between ICH burden and the severity of arterial SMC loss ( 67 ).…”

Section: Vascular Pathologymentioning

confidence: 99%

“…Here, Notch3 -KO mice exhibit a loss of mural cells, whereas Col4a1 -mutant mice show an increased number of mural cells in this zone with higher contractile protein content, a defect called “hypermuscularization.” Further genetic, functional, and computational modeling studies in Col4a1 -mutant mice provided evidence that arteriole SMC loss and hypermuscularization of the ACT zone act as mutually reinforcing vascular defects to cause ICH, with the excessive ACT zone muscularization raising intravascular pressure in the upstream feeding arteriole and promoting arteriolar rupture at the site of SMC loss ( Figure 3 ) ( 65 ). Molecular studies in Col4a1 -mutant mice suggest that arterial SMC loss is driven by increased TGF-β activity, whereas the hypermuscularization of the ACT zone arises from increased NOTCH3 activity ( 65 , 68 ). Regarding the capillary bed, 2D and 3D imaging in rodents revealed a small reduction in vascular length, branching density, and pericyte number, particularly in deep cortical layers and WM, in aged brains ( 59 , 60 ).…”

Section: Vascular Pathologymentioning

confidence: 99%

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

Dupré,

Drieu,

Joutel

2024

Journal of Clinical Investigation

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Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3 , HTRA1 , and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.

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Elevated TGFβ signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome

Cited by 7 publications

References 129 publications

TGFβ Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage

TGFβ Signaling Dysregulation May Contribute to COL4A1-Related Glaucomatous Optic Nerve Damage

PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease

Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

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