Brain Injury: Response to Injury Wound-Healing Mechanisms and Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus

Abstract

Embryonic genetic mechanisms are present in the brain and ready to be placed into action upon cellular injury, termed the response to injury wound-healing (RTIWH) mechanism. When injured, regional brain endothelial cells initially undergo activation and dysfunction with initiation of hemostasis, inflammation (peripheral leukocytes, innate microglia, and perivascular macrophage cells), proliferation (astrogliosis), remodeling, repair, and resolution phases if the injurious stimuli are removed. In conditions wherein the injurious stimuli are chronic, as occurs in obesity, metabolic syndrome, and type 2 diabetes mellitus, this process does not undergo resolution and there is persistent RTIWH with remodeling. Indeed, the brain is unique, in that it utilizes its neuroglia: the microglia cell, along with peripheral inflammatory cells and its astroglia, instead of peripheral scar-forming fibrocytes/fibroblasts. The brain undergoes astrogliosis to form a gliosis scar instead of a fibrosis scar to protect the surrounding neuropil from regional parenchymal injury. One of the unique and evolving remodeling changes in the brain is the development of enlarged perivascular spaces (EPVSs), which is the focus of this brief review. EPVSs are important since they serve as a biomarker for cerebral small vessel disease and also represent an impairment of the effluxing glymphatic system that is important for the clearance of metabolic waste from the interstitial fluid to the cerebrospinal fluid, and disposal. Therefore, it is important to better understand how the RTIWH mechanism is involved in the development of EPVSs that are closely associated with and important to the development of premature and age-related cerebrovascular and neurodegenerative diseases with impaired cognition.

A Closer Look at the Perivascular Unit in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus

“…During the remodeling phase in the response to injury wound healing (RTIWH) mechanism [64], multiple remodeling changes occur, including the development of EPVSs, which can be visualized on non-invasive T2-weighted MRI images. These changes are primarily located either in the basal ganglia or the centrum semiovale depending on the clinical disease state of the brain injury and response to injury wound-healing mechanism (Figure 16) [2,[64][65][66][67][68]. EPVS are most commonly viewed in the BG and CSO.…”

“…Further, Nielsen et al were able to demonstrate that nanogold particles staining of AQP4 by transmission electron immunochemistry were localized to the plasma membrane of the pvACef where they tightly adhered to the NVUs' pvACef basement membrane [86]. I have only had the opportunity to explore the AQP4 by immunohistochemistry in hepatic cirrhosis individuals and included images from the brains of those individuals with encephalopathy and EPVS (Figure 17) [9,64].…”

“…(D) In younger models, AQP4 is tightly polarized to the plasma membrane of the pvACef as compared to (E), which depicts a loss of AQP4 polarization in older models. Modified image provided with permission by CC 4.0 [64]. Scale bar = 500 µm.…”

“…Proper polarization and functioning of both the AQP4 water channels (AQP4) and dystroglycan (DG) at the pvACef are absolutely necessary for the normal functioning of both the NVU and PVU. Once pvACef or perisynaptic astrocytes become dysfunctional or lose their polarization of AQP4 or DG the pvACef will undergo detachment and separation from the NVU BEC and pericyte endfeet (Pcef) BMs and separate, which allows for not only NVU but also PVU dysfunction with increased permeability, and become increasingly vulnerable to the response to brain injury wound-healing mechanisms (Figure 15) [7,9,59,64,89]. In a past study of obese, insulin-resistant, 20-week-old female diabetic db/db models, I was able to demonstrate pvACef detachment and separation from the NVU BECs and Pcfps outer BM [7].…”

“…Also, Morrone et al proposed that venular amyloid is an important part of both CAA and AD or LOAD pathology [121]. Further, numerous mechanisms related to the pathophysiology of veins, which include EPVS, venous impaired cerebrovascular pulsatility due to the vascular stiffness of aging, and continued studies would allow for further insight into cerebral SVD, CAA, LOAD, and cerebrovascular dysfunction as an associated early remodeling change associated with multiple brain injuries that result in the response to injury woundhealing mechanisms to add further insight [64,120,121] and may lend further insight into the cerebrovascular dysfunction in SVD, CAA, and LOAD [120,121].…”