Investigation of the role of pericytes in hypertension-relatedcerebral small vessel disease

Introduction: The increase in the average life expectancy in society brings with it a decrease in cognitive capacity and the increase in the rate of dementia seen with aging as an important problem. The prevalence of occlusions in deep brain veins, small vessel disease, and white matter lesions grows as individuals age. Clinical research has demonstrated that these lesions significantly contribute to the decline in cognitive function. Hypertension (HT) is a chronic disease associated with small vessel disease, perivascular fibrosis and dementia. Perivascular fibrosis makes it difficult to clear waste materials from the brain. Recent studies suggest that pericytes may be responsible for this increased fibrosis. Objective: In this study, we aimed to investigate the effects of pericytes on blood pressure values, disease course, cognition and brain fibrosis and waste material clearance by triggering HT in a transgenic pericyte ablation mouse model. Method: To create conditional pericyte ablation, CreER+/- mice were crossed with Rosa26-DTA176+/+ mice. According to genotyping analysis, 28 animals that were CreER+Rosa26-DTA176+/+ positive were injected with tamoxifen for 2 days and their pericytes were ablated. 24 animals from the C57BL/6 breed were used as the control group. All animals were given angiotensin-II infusion of 1000ng/kg/day for 28 days by subcutaneous continuous infusion pump to create the HT model. Validation of the model was performed by measuring blood pressure from the tail cuff. In the last week of the v experiment, locomotor and cognitive changes were evaluated with open field, y-maze and novel object recognition tests. At the end of the experiment, all animals were injected with fluorescently labeled amyloid-beta (Aβ) via the cisterna magna. After 45 minutes, the clearance of Aβ from the brain in animals perfused was compared between the groups. Findings: At the end of the one-month model, blood pressure values of the animals increased significantly compared to the initial measurements. Blood pressure measurements tended to be lower in the groups with pericyte ablated. In the open field test results, the total number of squares covered was significantly reduced in the pericyte ablation groups compared to the normal pericyte groups. When working memory and novel object discrimination index were examined in cognitive tests, they were lower in the pericyte ablation hypertension group. Clearance of Aβ from the brain was performed by scanning the marker in the intraventricular, pial arteries, intraparenchymal and pial veins. After 45 minutes, Aβ was observed only in the veins in the normal pericyte group, while in the pericyte ablation group, it was found that it spread widely to the parenchyma but did not reach the veins. Conclusion: Pericyte ablation leads to lower blood pressure values in the hypertension model. It is also associated with significant locomotor slowness and delayed Aβ clearance and intraparenchymal accumulation. Therefore, healthy pericytes may be of critical importance in clearing toxic substances from the brain in the setting of HT and in protecting against dementia. Keywords: hypertension, cerebral small vessel disease, blood-brain-barrier, pericyte, fibrosis