, 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


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.


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



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.


  1. Avants BB, Epstein CL, Grossman M, Gee JC (2008) Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 12:26–41. CrossRefPubMedGoogle Scholar
  2. Avants BB, Tustison NJ, Song G, Cook PA, Klein A, Gee JC (2011) A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage 54:2033–2044. CrossRefPubMedGoogle Scholar
  3. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, A. Saltness R, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–189. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bolduc V, Drouin A, Gillis MA, Duquette N, Thorin-Trescases N, Frayne-Robillard I, Des Rosiers C, Tardif JC, Thorin E (2011) Heart rate-associated mechanical stress impairs carotid but not cerebral artery compliance in dyslipidemic atherosclerotic mice. Am J Physiol Heart Circ Physiol 301:H2081–H2092. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Breteler MM (2000) Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging 21:153–160CrossRefGoogle Scholar
  7. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562:578–582. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87:840–844CrossRefGoogle Scholar
  9. Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354:472–477. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Csiszar A, Tarantini S, Fülöp GA, Kiss T, Valcarcel-Ares MN, Galvan V, Ungvari Z, Yabluchanskiy A (2017) Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease. Geroscience 39:359–372. CrossRefPubMedPubMedCentralGoogle Scholar
  11. de la Torre JC (2002) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33:1152–1162CrossRefGoogle Scholar
  12. de Montgolfier O, Pinçon A, Pouliot P, Gillis MA, Bishop J, Sled JG, Villeneuve L, Ferland G, Lévy BI, Lesage F, Thorin-Trescases N, Thorin É (2019) High systolic blood pressure induces cerebral microvascular endothelial dysfunction, neurovascular unit damage, and cognitive decline in mice. Hypertension 73:217–228. CrossRefPubMedGoogle Scholar
  13. DeCarli C (2012) Cerebrovascular disease: assessing the brain as an end-organ of vascular disease. Nat Rev Cardiol 9:435–436. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Didion SP, Heistad DD, Faraci FM (2001) Mechanisms that produce nitric oxide-mediated relaxation of cerebral arteries during atherosclerosis. Stroke 32:761–766CrossRefGoogle Scholar
  15. Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623. CrossRefPubMedGoogle Scholar
  16. Dorr AE, Lerch JP, Spring S, Kabani N, Henkelman RM (2008) High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage 42:60–69. CrossRefPubMedGoogle Scholar
  17. Drouin A, Bolduc V, Thorin-Trescases N, Bélanger É, Fernandes P, Baraghis E, Lesage F, Gillis MA, Villeneuve L, Hamel E, Ferland G, Thorin E (2011a) Catechin treatment improves cerebrovascular flow-mediated dilation and learning abilities in atherosclerotic mice. Am J Physiol Heart Circ Physiol 300:H1032–H1043. CrossRefPubMedGoogle Scholar
  18. Drouin A, Farhat N, Bolduc V, Thorin-Trescases N, Gillis MA, Villeneuve L, Nguyen A, Thorin E (2011b) Up-regulation of thromboxane A(2) impairs cerebrovascular eNOS function in aging atherosclerotic mice. Pflugers Arch 462:371–383. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Drouin A, Thorin E (2009) Flow-induced dilation is mediated by Akt-dependent activation of endothelial nitric oxide synthase-derived hydrogen peroxide in mouse cerebral arteries. Stroke 40:1827–1833CrossRefGoogle Scholar
  20. Farkas E, Luiten PG (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64:575–611CrossRefGoogle Scholar
  21. Fleg JL, Strait J (2012) Age-associated changes in cardiovascular structure and function: a fertile milieu for future disease. Heart Fail Rev 17:545–554. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Fotuhi M, Do D, Jack C (2012) Modifiable factors that alter the size of the hippocampus with ageing. Nat Rev Neurol 8:189–202. CrossRefPubMedGoogle Scholar
  23. Fulop GA, Kiss T, Tarantini S, Balasubramanian P, Yabluchanskiy A, Farkas E, Bari F, Ungvari Z, Csiszar A (2018) Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. Geroscience 40:513–521. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Gendron ME, Théorêt JF, Mamarbachi AM, Drouin A, Nguyen A, Bolduc V, Thorin-Trescases N, Merhi Y, Thorin E (2010) Late chronic catechin antioxidant treatment is deleterious to the endothelial function in aging mice with established atherosclerosis. Am J Physiol Heart Circ Physiol 298:H2062–H2070. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Godbout JP, Johnson RW (2009) Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol Allergy Clin N Am 29:321–337. CrossRefGoogle Scholar
  26. Harada CN, Natelson Love MC, Triebel KL (2013) Normal cognitive aging. Clin Geriatr Med 29:737–752. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360. CrossRefPubMedGoogle Scholar
  28. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376 doi. CrossRefPubMedGoogle Scholar
  29. Iadecola C, Yaffe K, Biller J, Bratzke LC, Faraci FM, Gorelick PB, Gulati M, Kamel H, Knopman DS, Launer LJ, Saczynski JS, Seshadri S, Zeki al Hazzouri A (2016) Impact of hypertension on cognitive function: a scientific statement from the American Heart Association. Hypertension 68:e67–e94. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10:381–391CrossRefGoogle Scholar
  31. Katusic ZS, Austin SA (2014) Endothelial nitric oxide: protector of a healthy mind. Eur Heart J 35:888–894. CrossRefPubMedGoogle Scholar
  32. Kennedy KM, Raz N (2009) Pattern of normal age-related regional differences in white matter microstructure is modified by vascular risk. Brain Res 1297:41–56. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadžić S, Zlokovic BV (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci 20:406–416. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD (1993) Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43:192–197CrossRefGoogle Scholar
  36. Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 6:37–48. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Moore SM, Zhang H, Maeda N, Doerschuk CM, Faber JE (2015) Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury. Angiogenesis 18:265–281. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15:331–337. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Nation DA, Sweeney MD, Montagne A, Sagare AP, D’Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV (2019) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 25:270–276. CrossRefPubMedPubMedCentralGoogle Scholar
  40. O’Donnell M, Teo K, Gao P, Anderson C, Sleight P, Dans A, Marzona I, Bosch J, Probstfield J, Yusuf S (2012) Cognitive impairment and risk of cardiovascular events and mortality. Eur Heart J 33:1777–1786. CrossRefPubMedGoogle Scholar
  41. O’Rourke MF, Safar ME (2005) Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension 46:200–204. CrossRefPubMedGoogle Scholar
  42. Pouliot P, Gagnon L, Lam T, Avti PK, Bowen C, Desjardins M, Kakkar AK, Thorin E, Sakadzic S, Boas DA, Lesage F (2017) Magnetic resonance fingerprinting based on realistic vasculature in mice. Neuroimage 149:436–445. CrossRefPubMedGoogle Scholar
  43. Raignault A, Bolduc V, Lesage F, Thorin E (2017) Pulse pressure-dependent cerebrovascular eNOS regulation in mice. J Cereb Blood Flow Metab 37:413–424. CrossRefPubMedGoogle Scholar
  44. Rockman HA, Ross RS, Harris AN, Knowlton KU, Steinhelper ME, Field LJ, Ross J, Chien KR (1991) Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc Natl Acad Sci U S A 88:8277–8281CrossRefGoogle Scholar
  45. Salat DH, Kaye JA, Janowsky JS (1999) Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease. Arch Neurol 56:338–344CrossRefGoogle Scholar
  46. Schmidt D, von Hochstetter AR (1995) The use of CD31 and collagen IV as vascular markers. A study of 56 vascular lesions. Pathol Res Pract 191:410–414. CrossRefPubMedGoogle Scholar
  47. Stewart-Lee AL, Burnstock G (1991) Changes in vasoconstrictor and vasodilator responses of the basilar artery during maturation in the Watanabe heritable hyperlipidemic rabbit differ from those in the New Zealand White rabbit. Arterioscler Thromb 11:1147–1155CrossRefGoogle Scholar
  48. Taylor CA, Greenlund SF, McGuire LC, Lu H, Croft JB (2017) Deaths from Alzheimer’s disease - United States, 1999-2014. MMWR Morb Mortal Wkly Rep 66:521–526. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Toth P, Tarantini S, Csiszar A, Ungvari Z (2017) Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312:H1–H20. CrossRefPubMedGoogle Scholar
  50. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33:1732–1742. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Tucsek Z, Noa Valcarcel-Ares M, Tarantini S, Yabluchanskiy A, Fülöp G, Gautam T, Orock A, Csiszar A, Deak F, Ungvari Z (2017) Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment. Geroscience 39:385–406. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Tustison NJ, Avants BB, Cook PA, Zheng Y, Egan A, Yushkevich PA, Gee JC (2010) N4ITK: improved N3 bias correction. IEEE Trans Med Imaging 29:1310–1320. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7:65–74. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, Gerig G (2006) User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage 31:1116–1128. CrossRefPubMedGoogle Scholar
  55. Zlokovic BV (2002) Vascular disorder in Alzheimer’s disease: role in pathogenesis of dementia and therapeutic targets. Adv Drug Deliv Rev 54:1553–1559CrossRefGoogle Scholar
  56. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201. CrossRefPubMedGoogle Scholar
  57. Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12:723–738. CrossRefPubMedPubMedCentralGoogle Scholar

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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