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