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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
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. https://doi.org/10.1016/j.media.2007.06.004
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. https://doi.org/10.1016/j.neuroimage.2010.09.025
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. https://doi.org/10.1038/nature16932
Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535. https://doi.org/10.1038/nature08983
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. https://doi.org/10.1152/ajpheart.00706.2011
Breteler MM (2000) Vascular risk factors for Alzheimer’s disease: an epidemiologic perspective. Neurobiol Aging 21:153–160
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. https://doi.org/10.1038/s41586-018-0543-y
Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87:840–844
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. https://doi.org/10.1126/science.aaf6659
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. https://doi.org/10.1007/s11357-017-9991-9
de la Torre JC (2002) Alzheimer disease as a vascular disorder: nosological evidence. Stroke 33:1152–1162
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. https://doi.org/10.1161/HYPERTENSIONAHA.118.12048
DeCarli C (2012) Cerebrovascular disease: assessing the brain as an end-organ of vascular disease. Nat Rev Cardiol 9:435–436. https://doi.org/10.1038/nrcardio.2012.92
Didion SP, Heistad DD, Faraci FM (2001) Mechanisms that produce nitric oxide-mediated relaxation of cerebral arteries during atherosclerosis. Stroke 32:761–766
Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623. https://doi.org/10.1016/S0140-6736(08)60694-7
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. https://doi.org/10.1016/j.neuroimage.2008.03.037
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. https://doi.org/10.1152/ajpheart.00410.2010
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. https://doi.org/10.1007/s00424-011-0973-y
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 40:1827–1833
Farkas E, Luiten PG (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64:575–611
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. https://doi.org/10.1007/s10741-011-9270-2
Fotuhi M, Do D, Jack C (2012) Modifiable factors that alter the size of the hippocampus with ageing. Nat Rev Neurol 8:189–202. https://doi.org/10.1038/nrneurol.2012.27
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. https://doi.org/10.1007/s11357-018-0047-6
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. https://doi.org/10.1152/ajpheart.00532.2009
Godbout JP, Johnson RW (2009) Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol Allergy Clin N Am 29:321–337. https://doi.org/10.1016/j.iac.2009.02.007
Harada CN, Natelson Love MC, Triebel KL (2013) Normal cognitive aging. Clin Geriatr Med 29:737–752. https://doi.org/10.1016/j.cger.2013.07.002
Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360. https://doi.org/10.1038/nrn1387
Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376 doi. https://doi.org/10.1038/nn2003
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. https://doi.org/10.1161/HYP.0000000000000053
Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10:381–391
Katusic ZS, Austin SA (2014) Endothelial nitric oxide: protector of a healthy mind. Eur Heart J 35:888–894. https://doi.org/10.1093/eurheartj/eht544
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. https://doi.org/10.1016/j.brainres.2009.08.058
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. https://doi.org/10.1038/nn.4489
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479. https://doi.org/10.1101/gad.1971610
Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD (1993) Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43:192–197
Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 6:37–48. https://doi.org/10.2147/CLEP.S37929
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. https://doi.org/10.1007/s10456-015-9465-6
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. https://doi.org/10.1038/nm.1912
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. https://doi.org/10.1038/s41591-018-0297-y
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. https://doi.org/10.1093/eurheartj/ehs053
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. https://doi.org/10.1161/01.HYP.0000168052.00426.65
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. https://doi.org/10.1016/j.neuroimage.2016.12.060
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. https://doi.org/10.1177/0271678X16629155
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 88:8277–8281
Salat DH, Kaye JA, Janowsky JS (1999) Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease. Arch Neurol 56:338–344
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. https://doi.org/10.1016/S0344-0338(11)80727-2
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 11:1147–1155
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. https://doi.org/10.15585/mmwr.mm6620a1
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. https://doi.org/10.1152/ajpheart.00581.2016
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. https://doi.org/10.1038/jcbfm.2013.143
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. https://doi.org/10.1007/s11357-017-9981-y
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. https://doi.org/10.1109/TMI.2010.2046908
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. https://doi.org/10.2174/157015909787602823
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. https://doi.org/10.1016/j.neuroimage.2006.01.015
Zlokovic BV (2002) Vascular disorder in Alzheimer’s disease: role in pathogenesis of dementia and therapeutic targets. Adv Drug Deliv Rev 54:1553–1559
Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201. https://doi.org/10.1016/j.neuron.2008.01.003
Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12:723–738. https://doi.org/10.1038/nrn3114
Funding
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.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
de Montgolfier, O., Pouliot, P., Gillis, MA. et al. Systolic hypertension-induced neurovascular unit disruption magnifies vascular cognitive impairment in middle-age atherosclerotic LDLr−/−:hApoB+/+ mice. GeroScience 41, 511–532 (2019). https://doi.org/10.1007/s11357-019-00070-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-019-00070-6