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

Abstract

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.

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Acknowledgements

The authors gratefully acknowledge use of the services and facilities of the Koç University Research Center for Translational Medicine (KUTTAM), funded by the Republic of Turkey Ministry of Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Ministry of Development. We are also grateful to Prof. Dr. Turgay Dalkara for critically reading the manuscript.

Funding

This research is funded by Koç University – Seed Fund (SF.00051) of Prof. Yasemin Gürsoy Özdemir.

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EÖ and YCT designed and performed all experiments, analysed data and wrote the manuscript. ES, EBK, AT and EY performed experiments and contributed to manuscript editing. HYE, SK and MZ contributed to study design and supervision process. YGÖ initiated and supervised the study, provided financial support, and revised the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Esra Özkan.

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All experiments and procedures were applied according to the protocols and criterions approved by the Institutional Animal Care and Use Committee (IACUC) of Koç University with 2017.HADYEK.003 approval number, according to Directive 2010/63/EU of the European Parliament and of the Council on the Protection of Animals Used for Scientific Purposes. All experiments were reported compliance with the Animal Research: Reporting in Vivo Experiments (ARRIVE) guidelines.

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Özkan, E., Çetin-Taş, Y., Şekerdağ, E. et al. Blood–brain barrier leakage and perivascular collagen accumulation precede microvessel rarefaction and memory impairment in a chronic hypertension animal model. Metab Brain Dis (2021). https://doi.org/10.1007/s11011-021-00767-8

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Keywords

  • Blood–brain barrier
  • Collagen
  • Dementia
  • Pericyte
  • Spontaneously hypertensive rats
  • Valsartan