Elevated TGFβ signaling contributes to ocular anterior segment dysgenesis in Col4a1 mutant mice

Mao, Mao; Labelle‐Dumais, Cassandre; Tufa, Sara F.; Keene, Douglas R.; Gould, Douglas B.

doi:10.1016/j.matbio.2022.05.001

Cited by 9 publications

(19 citation statements)

References 140 publications

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“…Elevated TGF-β signaling has been shown to contribute to the ocular pathogenesis of Col4a1 mutant mice ( 36 ). Acute block of TGF-β receptors repaired defective myogenic tone of cerebral arteries from middle-aged Col4a1 +/G394V mice, implicating this pathway in the deficiency.…”

Section: Discussionmentioning

confidence: 99%

Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome

Yamasaki

Ali

Solano

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Gould syndrome is a rare multisystem disorder resulting from autosomal dominant mutations in the collagen-encoding genes COL4A1 and COL4A2. Human patients and Col4a1 mutant mice display brain pathology that typifies cerebral small vessel diseases (cSVDs), including white matter hyperintensities, dilated perivascular spaces, lacunar infarcts, microbleeds, and spontaneous intracerebral hemorrhage. The underlying pathogenic mechanisms are unknown. Using the Col4a1 +/G394V mouse model, we found that vasoconstriction in response to internal pressure—the vascular myogenic response—is blunted in cerebral arteries from middle-aged (12 mo old) but not young adult (3 mo old) animals, revealing age-dependent cerebral vascular dysfunction. The defect in the myogenic response was associated with a significant decrease in depolarizing cation currents conducted by TRPM4 (transient receptor potential melastatin 4) channels in native cerebral artery smooth muscle cells (SMCs) isolated from mutant mice. The minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP 2 ) is necessary for TRPM4 activity. Dialyzing SMCs with PIP 2 and selective blockade of phosphoinositide 3-kinase (PI3K), an enzyme that converts PIP 2 to phosphatidylinositol (3, 4, 5)-trisphosphate (PIP 3 ), restored TRPM4 currents. Acute inhibition of PI3K activity and blockade of transforming growth factor-beta (TGF-β) receptors also rescued the myogenic response, suggesting that hyperactivity of TGF-β signaling pathways stimulates PI3K to deplete PIP 2 and impair TRPM4 channels. We conclude that age-related cerebral vascular dysfunction in Col4a1 +/G394V mice is caused by the loss of depolarizing TRPM4 currents due to PIP 2 depletion, revealing an age-dependent mechanism of cSVD.

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Section: Discussionmentioning

confidence: 99%

Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome

Yamasaki

Ali

Solano

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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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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“…Although the pathogenic mechanisms contributing to Gould syndrome are largely unknown, we recently reported that elevated transforming growth factor beta (TGFβ) signaling contributes to ocular and central nervous system vascular pathologies in Col4a1 mutant mice. 33 – 35 …”

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confidence: 99%

“…We recently showed that TGFβ signaling is elevated in both the brain and developing anterior segments of Col4a1 mutant mice. 33 – 35 Reducing TGFβ signaling genetically (using heterozygous Tgfb1 or Tgfb2 null mice) or pharmacologically (using a pan-TGFβ neutralizing antibody) partially ameliorated ASD and cerebrovascular manifestations in Col4a1 mutant mice. 33 – 35 Notably, we showed distinct contributions of TGFβ1 and TGFβ2 to the ASD phenotypes in Col4a1 mutant mice, suggesting that they have different roles in ocular development, which might explain the partial protective effect seen in each model.…”

mentioning

confidence: 99%

“… 33 – 35 Reducing TGFβ signaling genetically (using heterozygous Tgfb1 or Tgfb2 null mice) or pharmacologically (using a pan-TGFβ neutralizing antibody) partially ameliorated ASD and cerebrovascular manifestations in Col4a1 mutant mice. 33 – 35 Notably, we showed distinct contributions of TGFβ1 and TGFβ2 to the ASD phenotypes in Col4a1 mutant mice, suggesting that they have different roles in ocular development, which might explain the partial protective effect seen in each model. 33 To determine whether elevated TGFβ signaling also contributes to elevated IOP and glaucoma associated with Gould syndrome, 23 , 24 , 29 here we tested the effect of genetically reducing TGFβ receptor 2 (TGFBR2), the common receptor for all three TGFβ ligands, 36 on glaucoma-relevant phenotypes in Col4a1 mutant mice.…”

mentioning

confidence: 99%

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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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Elevated TGFβ signaling contributes to ocular anterior segment dysgenesis in Col4a1 mutant mice

Cited by 9 publications

References 140 publications

Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome

Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome

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

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

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