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Piezo1 agonist restores meningeal lymphatic vessels, drainage, and brain-CSF perfusion in craniosynostosis and aged mice
Matt J. Matrongolo, … , Young-Kwon Hong, Max A. Tischfield
Matt J. Matrongolo, … , Young-Kwon Hong, Max A. Tischfield
Published November 2, 2023
Citation Information: J Clin Invest. 2024;134(4):e171468. https://doi.org/10.1172/JCI171468.
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Research Article Neuroscience Vascular biology Article has an altmetric score of 70

Piezo1 agonist restores meningeal lymphatic vessels, drainage, and brain-CSF perfusion in craniosynostosis and aged mice

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Abstract

Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associate with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in Twist1+/–:5xFAD transgenic Alzheimer’s disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show that Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest that CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.

Authors

Matt J. Matrongolo, Phillip S. Ang, Junbing Wu, Aditya Jain, Joshua K. Thackray, Akash Reddy, Chi Chang Sung, Gaëtan Barbet, Young-Kwon Hong, Max A. Tischfield

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Figure 2

CS affects MLV sprouting, expansion, and long-term maintenance.

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CS affects MLV sprouting, expansion, and long-term maintenance.
(A) Repr...
(A) Representative images from P17 mice. Sprouting and expansion of MLVs along the TVS is reduced in mice with CS and raised ICP. (B) Quantification of percent area fraction of Lyve-1 [Twist1+/+ (n = 10); Twist1+/– (n = 7)], number of sprouts [Twist1+/+ (n = 10); Twist1+/– (n = 6)], and levels of ICP at P17 [n = 5/genotype]. (C) Compared with controls (left), MLVs along the SSS and TVS (arrows) are hypoplastic in Twist1+/FLX:Sm22a-Cre:Prox1-tdTomato (right) and Twist1+/–:Prox1-tdTomato mice (center). Hotspots along the TVS are poorly formed or missing (asterisks). (D) Quantification of percent area fraction [Twist1FLX/+ and Twist1FLX/+:Sm22a-Cre (n = 6); Twist1+/+ (n = 9) and Twist1+/– (n = 8)] and average vessel diameters along the TVS [Twist1+/+ and Twist1+/– (n = 8)] and at hotspots [Twist1+/+ and Twist1+/– (n = 8)]. (E and F) A small subset of CS mice shows signs of vessel hyperplasia [Twist1+/– (n = 3)]. (G) In 8–10-month-old adults, dorsal MLVs are further regressed, especially at the sinus confluence and along the SSS (arrow). (H) Quantification of Lyve-1 percent area fraction [Twist1+/+ (n = 6); Twist1+/– (n = 9)], average vessel diameter along the TVS [Twist1+/+ (n = 6); Twist1+/– (n = 10)], and growth from the CoS [Twist1+/+ (n = 6); Twist1+/– (n = 10)]. (I) Basal MLVs along the SgS and PSS are hyperplastic in Twist1+/– mice with CS. (J) Quantification of average vessel diameter and the percent area fraction of MLVs along the PSS and SgS [Twist1+/+ (n = 10); Twist1+/– (n = 9)]. SSS, superior sagittal sinus; TVS, transverse sinus; CoS, confluence of sinuses; hsp, hotspot; SgS, sigmoid sinus; PSS, petrosquamosal sinus. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 2-tailed unpaired t test (B, D, H, and J), 1-way ANOVA with Tukey’s multiple comparison test (F). Scale bars: 200 μm (A); 1 mm (C); and 500 μm (E, G, and I).

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