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GeroScience

, Volume 41, Issue 5, pp 511–532 | Cite as

Systolic hypertension-induced neurovascular unit disruption magnifies vascular cognitive impairment in middle-age atherosclerotic LDLr−/−:hApoB+/+ mice

  • Olivia de Montgolfier
  • Philippe Pouliot
  • Marc-Antoine Gillis
  • Guylaine Ferland
  • Frédéric Lesage
  • Nathalie Thorin-Trescases
  • Éric ThorinEmail author
Original Article

Abstract

Cognitive functions are dependent upon intercommunications between the cellular components of the neurovascular unit (NVU). Vascular risk factors are associated with a more rapid rate of cognitive decline with aging and cerebrovascular diseases magnify both the incidence and the rate of cognitive decline. The causal relationship between vascular risk factors and injury to the NVU is, however, lacking. We hypothesized that vascular risk factors, such as hypertension and dyslipidemia, promote disruption of the NVU leading to early cognitive impairment. We compared brain structure and cerebrovascular functions of 1-year old (middle-aged) male wild-type (WT) and atherosclerotic hypertensive (LDLr−/−:hApoB+/+, ATX) mice. In addition, mice were subjected, or not, to a transverse aortic constriction (TAC) for 6 weeks to assess the acute impact of an increase in systolic blood pressure on the NVU and cognitive functions. Compared with WT mice, ATX mice prematurely developed cognitive decline associated with cerebral micro-hemorrhages, loss of microvessel density and brain atrophy, cerebral endothelial cell senescence and dysfunction, brain inflammation, and oxidative stress associated with blood-brain barrier leakage and brain hypoperfusion. These data suggest functional disturbances in both vascular and parenchymal components of the NVU. Exposure to TAC-induced systolic hypertension promoted cerebrovascular damage and cognitive decline in WT mice, similar to those observed in sham-operated ATX mice; TAC exacerbated the existing cerebrovascular dysfunctions and cognitive failure in ATX mice. Thus, a hemodynamic stress such as systolic hypertension could initiate the cascade involving cerebrovascular injury and NVU deregulation and lead to cognitive decline, a process accelerated in atherosclerotic mice.

Keywords

Hypertension 7T-MRI Senescence Apoptosis Transverse aortic constriction Endothelial function Blood-brain barrier Carotid stiffness VCID 

Notes

Grants

This research was supported by the Canadian Institutes of Health Research (MOP 133649, E.T.) and by the Foundation of the Montreal Heart Institute (E.T.).

Compliance with Ethical Standards

The study was approved by the Montreal Heart Institute ethics committee (ET No 2015-62-01).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Faculty of Medicine, Department of pharmacology and physiologyUniversité de MontréalMontrealCanada
  2. 2.Research CenterMontreal Heart InstituteMontrealCanada
  3. 3.Ecole Polytechnique de MontréalMontrealCanada
  4. 4.Faculty of Medicine, Department of nutritionUniversité de MontréalMontrealCanada
  5. 5.Faculty of Medicine, Department of surgeryUniversité de MontréalMontrealCanada

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