RESUMEN
Diabetes mediates endothelial dysfunction and increases the risk of Alzheimer's disease and related dementias. Diabetes also dysregulates the ET system. ET-1-mediated constriction of brain microvascular pericytes (BMVPCs) has been shown to contribute to brain hypoperfusion. Cellular senescence, a process that arrests the proliferation of harmful cells and instigates phenotypical changes and proinflammatory responses in endothelial cells that impact their survival and function. Thus, we hypothesized that ET-1 mediates BMVPC senescence and phenotypical changes in diabetes-like conditions. Human BMVPCs were incubated in diabetes-like conditions with or without ET-1 (1 µmol/L) for 3 and 7 days. Hydrogen peroxide (100 µmol/L H2O2) was used as a positive control for senescence and to mimic ischemic conditions. Cells were stained for senescence-associated ß-galactosidase or processed for immunoblotting and quantitative real-time PCR analyses. In additional experiments, cells were stimulated with ET-1 in the presence or absence of ETA receptor antagonist BQ-123 (20 µmol/L) or ETB receptor antagonist BQ-788 (20 µmol/L). ET-1 stimulation increased ß-galactosidase accumulation which was prevented by BQ-123. ET-1 also increased traditional senescence marker p16 protein and pericyte-specific senescence markers, TGFB1i1, PP1CA, and IGFBP7. Furthermore, ET-1 stimulated contractile protein α-SMA and microglial marker ostepontin in high glucose suggesting a shift toward an ensheathing or microglia-like phenotype. In conclusion, ET-1 triggers senescence, alters ETA and ETB receptors, and causes phenotypical changes in BMVPCs under diabetes-like conditions. These in vitro findings need to be further studied in vivo to establish the role of ETA receptors in the progression of pericyte senescence and phenotypical changes in VCID.
Asunto(s)
Encéfalo , Senescencia Celular , Endotelina-1 , Pericitos , Receptor de Endotelina A , Humanos , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Diabetes Mellitus/metabolismo , Endotelina-1/metabolismo , Endotelina-1/farmacología , Pericitos/metabolismo , Pericitos/efectos de los fármacos , Pericitos/patología , Fenotipo , Receptor de Endotelina A/metabolismo , Receptor de Endotelina A/genéticaRESUMEN
Vascular contributions to cognitive impairment/dementia (VCID) are a leading cause of dementia, a known neurodegenerative disorder characterized by progressive cognitive decline. Although diabetes increases the risks of stroke and the development of cerebrovascular disease, the cellular and vascular mechanisms that lead to VCID in diabetes are yet to be determined. A growing body of research has identified that cerebrovascular cells within the neurovascular complex display an array of cellular responses that impact their survival and reparative properties, which plays a significant role in VCID development. Specifically, endothelial cells and pericytes are the primary cell types that have gained much attention in dementia-related studies due to their molecular and phenotypic heterogeneity. In this review, we will discuss the various morphological subclasses of endothelial cells and pericytes as well as their relative distribution throughout the cerebrovasculature. Furthermore, the use of diabetic and stroke animal models in preclinical studies has provided more insight into the impact of sex differences on cerebral vascularization in progressive VCID. Understanding how cellular responses and sex differences contribute to endothelial cell and pericyte survival and function will set the stage for the development of potential preventive therapies for dementia-related disorders in diabetes.