Adaptation to intermittent hypoxia prevents the decrease in cerebral vascular density in rats with experimental Alzheimer’s disease
https://doi.org/10.24884/1682-6655-2021-20-2-59-64
Abstract
Introduction. Patients with Alzheimer’s disease (AD) have reduced cerebral vascular density (VD), which impairs blood flow to neurons and may contribute to progression of AD. Earlier we showed that prior adaptation to intermittent hypobaric hypoxia (IHH) prevented memory loss and degeneration of cortical neurons in rats with experimental AD (EAD).
The aim of this study was to test if IHH might prevent EAD-induced vascular rarefaction in rats.
Materials and methods. EAD was induced with bilateral injection of neurotoxic beta-amyloid peptide fragment (A) (25–35) into n. basalis magnocellularis. IHH was simulated at a 4,000 m altitude, for 4 hours a day, for 14 days. Brain blood vessels were stained by transcardiac infusion of Indian ink; brain sections were stained with 0.3 % cresyl violet by Nissle method. Vascular density was assessed in the cortex and hippocampus using the Infinity Analysis Software.
Results. In the EAD rats, VD was significantly decreased in the hippocampus (13.3±0.9 vs 17.8±1.0 in field of view, FOV, p<0.03) and in the cortex (17.3±1.5 vs 22.3±1.3 in FOV, p<0.03). AIH increased VD in the hippocampus to 27.0±3.5 in FOV (p=0.01) and in cortex to 26.0±1.1 in FOV (p<0.03). In EAD+AIH rats, VD did not differ significantly from the control rats neither in the hippocampus, nor in the cortex. AIH may stimulate angiogenesis through hypoxia inducible factor-1α-mediated expression of vascular endothelial growth factor and/or by increasing expression and activity of antioxidant enzymes.
Conclusion. One of the mechanisms of AIH beneficial effect in AD-related neurodegeneration is preserving the capability for compensatory angiogenesis in brain.
About the Authors
A. V. GoryachevaRussian Federation
Goryacheva Anna V. – researcher
8, Baltiyskaya str., Moscow, 125315
I. V. Barskov
Russian Federation
Barskov Igor V. – MD, associate Professor of the Department of Morphology and Pathology and head of Interdepartmental laboratory of Morphology
2, Krasnobogatyrskaya Str. Bldg. 2, Moscow, 107564
H. F. Downey
United States
Downey Harry Fred – PhD, Reagents Professor; Consultant
3500 Camp Bowie Blvd, Fort Worth 76107
76, Lenina pr., Chelyabinsk, 454080
Eu. B. Manukhina
Russian Federation
Manukhina Eugenia B., PhD, DSc, Professor, Head Researcher; Leading Researcher; Adjunct Professor
8, Baltiyskaya str., Moscow, 125315
3500 Camp Bowie Blvd, Fort Worth 76107, USA
76, Lenina pr., Chelyabinsk, 454080
References
1. Solis E, Hascup KN, Hascup ER. Alzheimer’s Disease: The link between amyloid-β and neurovascular dysfunction. J Alzheimers Dis. 2020;76(4):1179–1198. Doi: 10.3233/JAD-200473.
2. Kim HW, Hong J, Jeon JC. Cerebral small vessel disease and Alzheimer’s disease: A review. Front Neurol. 2020; 25(11):927. Doi: 10.3389/fneur.2020.00927.
3. Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 2011;37(1):56–74. Doi: 10.1111/j.1365-2990.2010.01139.x.
4. Fischer VW, Siddiqi A, Yusufaly Y. Altered angioarchitecture in selected areas of brains with Alzheimer’s disease. Acta Neuropathol (Berl). 1990;79(6):672–679. Doi: 10.1007/BF00294246.
5. Goryacheva AV, Kruglov SV, Pshennikova MG, Smirin BV, Malyshev IYu, Barskov IV, Viktorov IV, Downey HF, Manukhina EB. Adaptation to intermittent hypoxia restricts nitric oxide overproduction and prevents beta-amyloid toxicity in rat brain. Nitric Oxide. 2010;23(4):289–299. Doi: 10. 1016/j.niox.2010.08.005.
6. Manukhina EB, Downey HF, Shi X, Mallet RT. Intermittent hypoxia training protects cerebrovascular function in Alzheimer’s disease. Exp Biol Med. 2016;241(12):1351–1363. Doi: 10.1177/1535370216649060.
7. Кардио-, вазо- и нейропротекторные эффекты адаптации к гипоксии: роль оксида азота: монография / Е. Б. Манухина, И. Ю. Малышев, Р. Т. Маллет, Г. Ф. Дауни. – М.: Сам Полиграфист, 2019. – C. 152. [Manukhina EB, Malyshev IYu, Mallet RT, Cardio-, vaso- and neuroprotective effects of adaptation to hypoxia: Role of nitric oxide. Moscow, Sam Polygraphist, 2019:152. (In Russ.)].
8. Harik SI, Hritz MA, LaManna JC. Hypoxia-induced brain angiogenesis in the adult rat. J Physiol (Lond.). 1995; 485 (Pt 2):525–530. Doi: 10.1113/jphysiol.1995.sp020748.
9. Манухина Е. Б., Соколова И. А., Родионов И. М. Изменение плотности сосудистой сети поверхности коры головного мозга у крыс при экспериментальной гипертонии и адаптации к высоте // Кардиология. – 1982. – № 10. – C. 118. [Manukhina EB, Sokolova IA, Rodionov IM. Changed vascular density on the brain surface in rats with experimental hypertension and after adaptation to high altitude. Kardiologiya. 1982;(10):118. (In Russ.]).
10. Prewitt RL, Cardoso SS, Wood WB. Prevention of arteriolar rarefaction in the spontaneously hypertensive rat by exposure to simulated high altitude. J Hypertens. 1986;4(6):735–740. Doi: 10.1097/00004872-198612000-00008.
11. Кошелев В. Б., Пинелис В. Г., Вакулина Т. П. и др. Влияние адаптации к высотной гипоксии на развитие структурных изменений резистивных сосудов у спонтанно-гипертензивных крыс // Кардиология. – 1985. – Т. 25. – С. 80–84. [Koshelev VB, Pinelis VG, Vakulina TP, Markov HM, Rodionov IM. Effect of adaptation to high-altitude hypoxia on development of structural changes in resistance blood vessels in spontaneously hypertensive rats. Kardiologiya. 1985;(25):80–84. (In Russ.)].
12. Aliev G, Gasimov E, Obrenovich ME, Fischbach K, Shenk JC, Smith MA, Perry G. Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer’s disease. Vasc Health Risk Manag. 2008;4(3):721–730. Doi: 10.2147/vhrm.s2608.
13. Kataoka K, Hashimoto H, Kawabe J, Higashiyama S, Akiyama H, Shimada A, Kai T, Inoue K, Shiomi S, Kiriike N. Frontal hypoperfusion in depressed patients with dementia of Alzheimer type demonstrated on 3DSRT. Psychiatry Clin Neurosci. 2010;64(3):293–298. Doi: 10.1111/j.1440-1819.2010.02083.x.
14. Bailey TL, Rivara CB, Rocher AB, Hof PR. The nature and effects of cortical microvascular pathology in aging and Alzheimer’s disease. Neurol. Res. 2004;26(5):573–578. Doi: 10.1179/016164104225016272.
15. Lee GD, Aruna JH, Barrett PM, Lei DL, Ingram DK, Mouton PR. Stereological analysis of microvascular parameters in a double transgenic model of Alzheimer’s disease. Brain Res Bull. 2005;65(4):317–322. Doi: 10.1016/j.brainresbull.2004.11.024.
16. de la Torre J.C. Vascular basis of Alzheimer’s pathogenesis. Ann N Y Acad Sci. 2002;(977):196–215. Doi: 10.1111/j.1749-6632.2002.tb04817.x.
17. Lederman RJ, Mendelson FO, Anderson RD, Saucedo J, Tenaglia A, Hermiller J. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomized trial. Lancet. 2002;359(9323):2053–2058. Doi: 10.1016/s0140-6736(02)08937-7.
18. Pecher P, Schumacher BA. Angiogenesis in ischemic human myocardium: clinical results after 3 years. Ann Thorac Surg. 2000;69(5):1414–1419. Doi: 10.1016/s0003-4975 (00)01162-0.
19. Tsunumi Y, Takeshita S, Chen D, Keaney M, Rossow S. Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Cirсulation. 1996;94(12):3281– 3290. Doi: 10.1161/01.cir.94.12.3281.
20. Wissink MJ, Beernink R, Poot AA, Engbers G, Beugeling T. Improved endothelization of vascular grafts by local release of growth factors from heparinized collagen matrices. J Contr Rel. 2000;64(1-3):103–114. Doi: 10.1016/s0168-3659(99)00145-5.
21. Boyer M, Townsend LE, Vogel L, Falk J, Reitz-Vick D, Trevor K. Isolation of endothelial cells from human peripheral blood. J Vasc Surg. 2000;31(1 Pt 1):181–189. Doi: 10.1016/s0741-5214(00)70080-2.
22. Mueller XM, Tevaearai H, Chaubert P, Genton CY, Sergesser L. Mechanism of action of transmyocardial revascularization. Schweiz Med Wochenschr. 1999;129(48):1889–1892.
23. LaManna JC, Chavez JC, Pichiule P. Structural and functional adaptation to hypoxia in the rat brain. J Exper Biol. 2004;207(Pt 18):3163–3169. Doi: 10.1242/jeb.00976. PMID: 15299038.
24. Lauro K.L., LaManna J.C. Adequacy of cerebral vascular remodeling following three weeks of hypobaric hypoxia. Examined by an integrated composite analytical model. Adv Exp Med Biol. 1997;(411):369–376. Doi: 10.1007/978-1-4615-5865-1_47.
25. Harik N, Harik SI, Kuo NT, Sakai K, Przybylski RJ, LaManna JC. Time course and reversibility of the hypoxiainduced alterations in cerebral vascularity and cerebral capillary glucose transporter density. Brain Res. 1996;21;737(1–2): 335–338. Doi: 10.1016/0006-8993(96)00965-1.
26. Harik SI, Hritz MA, LaManna JC. Hypoxia-induced brain angiogenesis in the adult rat. J Physiol (Lond.). 1995; 485(Pt 2)(Pt 2):525–530. Doi: 10.1113/jphysiol.1995.sp020748.
27. Ashok BS, Ajith TA, Sivanesan S. Hypoxia-inducible factors as neuroprotective agent in Alzheimer’s disease. Clin Exp Pharmacol Physiol. 2017;44(3):327–334. Doi: 10.1111/1440-1681.12717.
28. Correia SC, Carvalho C, Cardoso S, Santos RX, Plá- cido AI, Candeias E, Duarte AI, Moreira PI. Defective HIF signaling pathway and brain response to hypoxia in neurodegenerative diseases: not an «iffy» question!. Curr Pharm Des. 2013;19(38):6809–6822. Doi: 10.2174/1381612811319380013.
29. Ray PS, Estrada-Hernandez T, Sasaki H, Zhu L, Maulik N. Early effects of hypoxia/ reoxygenation on VEGF, ang-1, ang-2 and their receptors in the rat myocardium: implications for myocardial angiogenesis. Mol Cell Biochem. 2000;213(1– 2):145–153. Doi: 10.1023/a:1007180518474.
30. Rizzoni D, Rodella L, Porteri E, Rezzani R, Guelfi D, Piccoli A, Castellano M, Muiesan ML, Bianchi R, Rosei EA. Time course of apoptosis in small resistance arteries of spontaneously hypertensive rats. J Hypertens. 2000;18(7):885–891. Doi: 10.1097/00004872-200018070-00010.
31. Kobayashi N, DeLano FA, Schmid-Schönbein GW. Oxidative stress promotes endothelial cell apoptosis and loss of microvessels in the spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol. 2005;25(10):2114-2121. Doi: 10.1161/01.ATV.0000178993.13222.f2.
32. Манухина Е. Б., Горячева А. В., Барсков И. В. и др. Предупреждение нейродегенеративного повреждения мозга крыс при экспериментальной болезни Альцгеймера с помощью адаптации к гипоксии // Росс. физиол. журн. им. И. М. Сеченова. 2009;95(7):706–715. [Manukhina EB, Goriacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SIu, Pokidyshev DA, Malyshev IIu. Prevention of the brain neurodegeneration in rats with experimental Alzheimer’s disease by adaptation to hypoxia. Ross Fiziol Zh Im I M Sechenova. 2009;95(7):706–715. (In Russ.]).
Review
For citations:
Goryacheva A.V., Barskov I.V., Downey H.F., Manukhina E.B. Adaptation to intermittent hypoxia prevents the decrease in cerebral vascular density in rats with experimental Alzheimer’s disease. Regional blood circulation and microcirculation. 2021;20(2):59-64. (In Russ.) https://doi.org/10.24884/1682-6655-2021-20-2-59-64