Vascular endotelial dysfunction is a pathogenetic factor in the development of neurodegenerative diseases and cognitive impairment

Abstract

The amount of publications devoted to the endothelial cells, on the one hand, and neurological diseases, on the other hand, has been growing rapidly in recent years. Nevertheless, the relationship between the endothelial monolayer and the cells of the nervous system remains poorly studied. This review presents the available information about endothelial markers, molecular and cellular mechanisms for maintaining the integrity of the endothelial monolayer and the violations in some acute and chronic neuropsychiatric diseases. At the molecular level, the most important pathogenetic link in endothelial dysfunction is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species. Genetic and epigenetic factors that cause these disorders and their cause-and-effect relationships are considered. Of the genetic diseases, the most studied are monogenic diseases associated with impaired blood-brain barrier integrity: this is a deficiency of protein molecules that ensure glucose transport, structural and functional integrity of tight junctions and the basement membrane of endothelial cells themselves, as well as mutations in pericytes and smooth muscle cells. Mutations that increase the risk of developing known neurodegenerative diseases, but are also the cause of cerebrovascular pathology, are less studied. The small vessel diseases constitute a whole group of primarily epigenetically caused diseases, the clinical consequence of which is often vascular dementia. Special attention is paid to one of the least studied problems—the pathogenesis of toxicological diseases that occur at different times after acute and chronic organophosphate poisoning. Microangiopathies caused by damage to the endothelium in the central and peripheral nervous systems can be the main cause for the development of delayed effects in organophosphate poisoning. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of the nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.

Serum Albumin in Health and Disease: Esterase, Antioxidant, Transporting and Signaling Properties

“…Interactions between the BBB, cerebral blood vessels, neurons, astrocytes, microglia and pericytes form a dynamic functional neurovascular unit. Damage to the cerebral cortex as a result of trauma, intoxication, ischemia or infection can lead to the progression of post-traumatic epilepsy (PTE), one of the most common neurological disorders—the pathogenesis of which is closely related to distortion of BBB integrity [ 261 , 262 ]. This, in turn, leads to the leaking of plasma components into the brain parenchyma and increased excitability of neurons—firstly as a result of a primary increase in K + and glutamate levels; then, as conjugated mechanisms are launched, extravasated albumin is absorbed by astrocytes through TGF-βR and leads to Smad2-mediated suppression of potassium channel Kir4.1, whereas astrocytic TNF-α initiates a decrease in expression of the glutamate transporter EAAT-2.…”

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

“…Metabolic dysfunction often affects microvascular ECs through albumin modifications, along with oxidative stress and inflammation, and promotes the damage of endothelial integrity followed by albumin penetration to the brain parenchyma [ 292 ]. The problem of prevention of neurodegenerative diseases such as PD, and therapeutic care for patients with clinical signs of these diseases should be carried out taking into account the “endothelial” constituent of pathogenesis [ 223 , 255 ]. In this regard, we suggest that the Braak dual hit hypothesis should be modified to the ‘triple hit hypothesis’; the pathogenesis resembles a ‘three lane highway’ Figure 3 .…”

“…Vascular defects may occur at an early age, affecting brain maturation, but may also appear at a later age, participating in neurodegenerative processes, including PD ( Table 1 ). More and more recent data indicate that vascular disorders largely determine the pathogenesis of neurological diseases throughout life [ 221 , 222 , 223 ].…”

“…The problem of prevention of neurodegenerative diseases, such as PD, and therapeutic care for patients with clinical signs of these diseases should be carried out taking into account the endothelial component of pathogenesis [ 223 ]. In this regard, it should be noted that at present special attention is paid to the peculiarities of lifestyle, in particular, indicators of the quality of the diet, food components and its calorie content.…”