One Mesmerizing Image, Six Cells, and a Space: The Story of Reactive Perivascular Astroglia, Enlarged Perivascular Spaces, and Small Vessel Disease

Enlarged perivascular spaces (EPVS) within the perivascular unit (PVU) provide a holding space, which provides a crossroad intersection. These EPVS provide a space for multiple cell cell contact interactions and communications for the six cells discussed in this narrative review. These six cells include the brain endothelial cells, mural supportive pericytes, and the supportive perivascular astrocyte endfeet (pvACef) to provide the 1st barrier of the blood-brain barrier of the neurovascular unit and the resident perivascular macrophage of the EPVS along with the outermost barrier pvACef cells of the PVU that provide the 2nd and final barrier to prevent neuroinflammation and the delivery of excess fluids and neurotoxins to the interstitium of the neural parenchymal cells. The final two cells are represented by the interrogating and/or reactive microglia and neurons along with their synapses to provide brain homeostasis. When these cells become damaged or dysfunctional due to multiple injurious species, they contribute to EPVS that are associated with many neurological diseases including both neurodevelopmental and neurodegenerative disorders that are associated with small vessel disease. The use of multiple transmission electron microscopic images along with illustrations are utilized to better understand the different functional and aberrant structural remodeling mechanisms. Indeed, the neuroglia perivascular and perisynaptic astrocytes are at the very center of providing not only the mesmerizing image but also play an important and critical role in neurodevelopmental and neurodegenerative diseases. The primary goal of this narrative review is to increase our holistic understanding of ultrastructural remodeling changes and functional mechanistic knowledge of these cells and spaces.