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Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRβ^+/- mice.

ABSTRACT: The receptor tyrosine kinase PDGFRβ is essential for pericyte migration to the endothelium. In mice lacking one allele of PDGFRβ (PDGFRβ^+/-), previous reports have described an age-dependent loss of pericytes in the brain, leading to cerebrovascular dysfunction and subsequent neurodegeneration reminiscent of that seen in Alzheimer's disease and vascular dementia. We examined 12-20-month-old PDGFRβ^+/- mice to better understand how pericyte loss affects brain microvascular structure and perfusion in vivo. We observed a mild reduction of cortical pericyte number in PDGFRβ^+/- mice (27% fewer cell bodies) compared to controls, but no decrease in pericyte coverage of the endothelium. This mild degree of pericyte loss caused no discernable change in cortical microvascular density, length, basal diameter or reactivity to hypercapnia. Yet, it was associated with an increase in basal blood cell velocity, primarily in pre-capillary arterioles. Taken together, our results suggest that mild pericyte loss can lead to aberrant cerebral blood flow despite a lack of apparent effect on microvascular structure and reactivity.

SUBMITTER: Watson AN

PROVIDER: S-EPMC7820684 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRβ+/- mice.

Watson Ashley N AN Berthiaume Andree-Anne AA Faino Anna V AV McDowell Konnor P KP Bhat Narayan R NR Hartmann David A DA Shih Andy Y AY

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20200127 12

The receptor tyrosine kinase PDGFRβ is essential for pericyte migration to the endothelium. In mice lacking one allele of PDGFRβ (PDGFRβ+/-), previous reports have described an age-dependent loss of pericytes in the brain, leading to cerebrovascular dysfunction and subsequent neurodegeneration reminiscent of that seen in Alzheimer's disease and vascular dementia. We examined 12-20-month-old PDGFRβ+/- mice to better understand how pericyte loss affects brain microvascular st ...[more]

PMID: 31987006

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Project description:The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB. The brain microvascular fragments were isolated from mice with different genotypes, each represented by 3-4 biological replicates. Genotypes 1-2: Platelet derived growth factor-B (PDGF-B) retention-motif knockout (pdgfbret/ret) represent the pericyte-deficient situation, and the heterozygous mice (pdgfbret/+) are used as controls. Genotypes 3-4: Hypomorphic PDGF-B mutants that rescue pdgfb-/- null mice, in which a one copy of a conditionally silent human PDGF-B transgene targeted to the Rosa 26 locus (R26P) is turned on by endothelial-specific expression of Cre recombinase. In this data set these mice are named as Tie2Cre, R26P+/0, pdgfb-/- (representing the pericyte-deficient situation). Mice wt for pdgfb (pdgfb+/+) and carrying one silent copy of R26P (R26P+/0), are used as controls. Genotype 5: Adult Notch3+/+ wildtype (WT).

Project description:Dynamic Functional Connectivity (DFC) analysis is a promising approach for the characterization of brain electrophysiological activity. In this study, we investigated abnormal alterations due to mild Traumatic Brain Injury (mTBI) using DFC of the source reconstructed magnetoencephalographic (MEG) resting-state recordings. Brain activity in several well-known frequency bands was first reconstructed using beamforming of the MEG data to determine ninety anatomical brain regions of interest. A DFC graph was formulated using the imaginary part of phase-locking values, which were obtained from 30 mTBI patients and 50 healthy controls (HC). Subsequently, we estimated normalized Laplacian transformations of individual, statistically and topologically filtered quasi-static graphs. The corresponding eigenvalues of each node synchronization were then computed and through the neural-gas algorithm, we quantized the evolution of the eigenvalues resulting in distinct network microstates (NMstates). The discrimination level between the two groups was assessed using an iterative cross-validation classification scheme with features either the NMstates in each frequency band, or the combination of the so-called chronnectomics (flexibility index, occupancy time of NMstate, and Dwell time) with the complexity index over the evolution of the NMstates across all frequency bands. Classification performance based on chronnectomics showed 80% accuracy, 99% sensitivity, and 49% specificity. However, performance was much higher (accuracy: 91-97%, sensitivity: 100%, and specificity: 77-93%) when focusing on the microstates. Exploring the mean node degree within and between brain anatomical networks (default mode network, frontoparietal, occipital, cingulo-opercular, and sensorimotor), a reduced pattern occurred from lower to higher frequency bands, with statistically significant stronger degrees for the HC than the mTBI group. A higher entropic profile on the temporal evolution of the modularity index was observed for both NMstates for the mTBI group across frequencies. A significant difference in the flexibility index was observed between the two groups for the β frequency band. The latter finding may support a central role of the thalamus impairment in mTBI. The current study considers a complete set of frequency-dependent connectomic markers of mTBI-caused alterations in brain connectivity that potentially could serve as markers to assess the return of an injured subject back to normality.

Dataset Information

Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRβ^+/- mice.

Publications

Mild pericyte deficiency is associated with aberrant brain microvascular flow in aged PDGFRβ<sup>+/-</sup> mice.

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