Three-dimensional remodeling of functional cerebrovascular architecture and gliovascular unit in leptin receptor-deficient mice

Abstract

The cerebrovascular sequelae of diabetes render victims more susceptible to ischemic stroke, vascular cognitive impairment, and Alzheimer's disease. However, limited knowledge exists on the progressive changes in cerebrovascular structure and functional remodeling in type 2 diabetes. To ascertain the impact of diabetes on whole-brain cerebrovascular perfusion, leptin-receptor-deficient mice were transcardially injected with tomato-lectin before sacrifice. The whole brain was clarified by the Fast free-of-acrylamide clearing tissue technique. Functional vascular anatomy of the cerebrum was visualized by light-sheet microscopy, followed by analysis in Imaris software. We observed enhanced neovascularization in adult db/db mice, characterized by increased branch level and loop structures. Microvascular hypoperfusion was initially detected in juvenile db/db mice, suggesting early onset of insufficient microcirculation. Furthermore, gliovascular unit remodeling was verified by loss of pericytes and overactivation of microglia and astrocytes in adult diabetic mice. However, the integrity of the blood-brain barrier (BBB) was fundamentally preserved, as shown by a lack of extravasation of IgG into the brain parenchyma. In summary, we, for the first time, reveal that functional cerebrovascular remodeling occurs as early as four weeks in db/db mice and the deficit in gliovascular coupling may play a role in cerebral hypoperfusion before BBB breakdown in 16-week-old db/db mice.

Rapid and fully automated blood vasculature analysis in 3D light-sheet image volumes of different organs

“…Hence, LSFM followed by automated VesselExpress analysis can uncover subtle vascular changes in the brain associated with a metabolic disease. Interestingly, mice with a defect in a related protein, the leptin receptor (db/db), which are characterized by obesity and diabetes, were recently shown to reveal a biphasic vascular development with a juvenile hypovascularization followed by aberrant hypervascularization in later adulthood 26 , although reported densities for branch points in that earlier study assessed by LSFM were lower than our data (Fig. 3A) and data reported elsewhere in the literature 7 .…”

Development and validation of prediction models for neurocognitive disorders in adult patients admitted to the ICU with sleep disturbance

“…43,45 We did not test these specific cytokines, but these were commonly incorporated clinical coagulation parameters, which may be conducive as universally and easily available predictive biomarkers. Similarly, increased blood glucose manifested as diabetes was an important predictor of the risk of NCDs 46 ; it has previously been considered a risk factor for delirium. 47 As shown by the results, diabetes was also an independent risk factor.…”

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

“…No changes in microglia number are detected in young (6-week-old) db/db mice either in the cerebral cortex or the hippocampus [213], whereas older (14-36 weeks) db/ db mice have increased number of microglia with augmented cell volume and amoeboid phenotype in comparison with WT mice in the same regions [213][214][215][216][217][218][219]. In the hypothalamus, db/db mice have similar numbers of microglia but with more ramified processes, as well as significantly lower transcription of Atf3, Itgax, Rab4a, IL-1β and TNF-α compared with WT mice [165].…”

“…In addition, invasion of amoeboid microglia into the neurovascular unit in db/db mice was also described [224]. These infiltrating microglia have an increased number of aberrant mitochondria, which might be responsible for their increased ROS production [224], and their somas have a shorter distance to the nearest microvessels compared to WT mice, which suggests hyperglycemia-induced, microglia-mediated vascular inflammation [219].…”