Blood–brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model

• Published in: Metabolic brain disease 2021-12, Vol.36 (8), p.2553-2566
• Main Authors: Özkan, Esra, Çetin-Taş, Yağmur, Şekerdağ, Emine, Kızılırmak, Ali B., Taş, Ali, Yıldız, Erdost, Yapıcı-Eser, Hale, Karahüseyinoğlu, Serçin, Zeybel, Müjdat, Gürsoy-Özdemir, Yasemin
• Format: Article
• Language: English
• Subjects: Accumulation; Albumins; Animal models; Animals; Astrocytes; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - metabolism; Breakdown; Cognition; Cognitive ability; Collagen; Collagen (type I); Collagen - metabolism; Dementia; Dementia disorders; Disease Models, Animal; Endothelial cells; Endothelial Cells - metabolism; Extracellular matrix; Hypertension; Immunofluorescence; Impairment; Leakage; Memory; Metabolic Diseases; Microvasculature; Microvessels - metabolism; Neurology; Neurosciences; Object recognition; Oncology; Original Article; Pattern recognition; Pericytes; Rarefaction; Rats; Rats, Wistar; Transforming growth factor-b1; Vascular dementia
• ISSN: 0885-7490; 1573-7365
• DOI: 10.1007/s11011-021-00767-8

Hypertension (HT) is one of the main causes of vascular dementia, lead to cognitive decline. Here, we investigated the relationship between cerebral microvessels, pericytes, extracellular matrix (ECM) accumulation, blood–brain barrier (BBB) breakdown, and memory impairment at mid-life in a chronic hypertension animal model. Spontaneously hypertensive rats (SHRs) ( n  = 20) are chosen for the model and age matched Wistar rats ( n  = 16) as controls. Changes in brain microvasculature and in vitro experiments are shown with immunofluorescence studies and cognition with open field, novel object recognition, and Y maze tests. There was a significant reduction in pericyte coverage in SHRs ( p  = 0.021), while the quantitative parameters of the cerebral microvascular network were not different between groups. On the other hand, parenchymal albumin leakage, as a Blood–brain barrier (BBB) breakdown marker, was prominent in SHRs ( p  = 0.023). Extracellular matrix (ECM) components, collagen type 1, 3 and 4 were significantly increased (accumulated) around microvasculature in SHRs ( p  = 0.011, p  = 0.013, p  = 0.037, respectively). Furthermore, in vitro experiments demonstrated that human brain vascular pericytes but not astrocytes and endothelial cells secreted type I collagen upon TGFβ1 exposure pointing out a possible role of pericytes in increased collagen accumulation around cerebral microvasculature due to HT. Furthermore, valsartan treatment decreased the amount of collagen type 1 secreted by pericytes after TGFβ1 exposure. At the time of evaluation, SHRs did not demonstrate cognitive decline and memory impairments. Our results showed that chronic HT causes ECM accumulation and BBB leakage before leading to memory impairments and therefore, pericytes could be a novel target for preventing vascular dementia.