Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice
Milagros C. Romay, … , Beth A. Kozel, M. Luisa Iruela-Arispe
Milagros C. Romay, … , Beth A. Kozel, M. Luisa Iruela-Arispe
Published November 28, 2023
Citation Information: J Clin Invest. 2024;134(2):e166134. https://doi.org/10.1172/JCI166134.
View: Text | PDF
Research Article Neuroscience Vascular biology

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice

Abstract

Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.

Authors

Milagros C. Romay, Russell H. Knutsen, Feiyang Ma, Ana Mompeón, Gloria E. Hernandez, Jocelynda Salvador, Snezana Mirkov, Ayush Batra, David P. Sullivan, Daniele Procissi, Samuel Buchanan, Elise Kronquist, Elisa A. Ferrante, William A. Muller, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Craig Horbinski, Elisabeth Tournier‑Lasserve, Adam M. Sonabend, Farzaneh A. Sorond, Michael M. Wang, Manfred Boehm, Beth A. Kozel, M. Luisa Iruela-Arispe

×

Figure 3

Notch3 deficiency leads to vascular dilation and tortuosity in the middle cerebral artery.

Options: View larger image (or click on image) Download as PowerPoint
Notch3 deficiency leads to vascular dilation and tortuosity in the middl...
(A) Schema of experimental analysis whereby micro-CT overlay of the brain vasculature of Notch3–/– (red) and control (white) mice identifies abnormalities. (B) Coronal and inferior micro-CT overlay of Notch3–/– and control animals at 18 months. Yellow arrows indicate tortuosity and aneurysms in Notch3–/– compared with control. Scale bars: 1000 μm (left), 500 μm (right). (C) Schema of the regions of middle cerebral artery (MCA) measured in D. (D) Volumetric analysis of the MCA from the circle of Willis to 3,000 μm in Z axis (from the MCA branch point upward) in control and Notch3–/–. Maximum-intensity projections of MCA were color-coded by volume and overlaid on the base micro-CT visualization (white) in the lateral view. Yellow arrows indicate tortuosity. Scale bars: 500 μm. (E) Quantification of MCA volumes from Notch3–/– and control littermates at 18 months. n = 4–6; Mann-Whitney test. (F) Quantification of tortuosity index for the MCA in a cohort of control and Notch3–/– animals. n = 4–6; Welch’s t test.