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Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats

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Abstract

A causative role of blood-brain barrier (BBB) impairment is suggested in the pathogenesis of vascular dementia with leakage of serum components from small vessels leading to neuronal and glial damage. We examined the BBB function of young adult spontaneously hypertensive rats (SHR) in order to determine earlier changes in the BBB in chronic hypertension. SHR and stroke-prone SHR (SHRSP) were injected with horseradish peroxidase (HRP) as an indicator of BBB function and compared with Wistar Kyoto rats (WKY). The brain tissues were further examined with cationized ferritin, a marker for evaluating glycocalyx. The staining for HRP was distributed around the vessels in the hippocampal fissure of SHR and SHRSP, but not in WKY. With electron microscopy, the extravasated reaction product of HRP appeared in abluminal pits of the endothelial cells of arterioles and within the basal lamina in the hippocampus, but not the cerebral cortex, of SHR and SHRSP. On the contrary, the reaction product of HRP was never seen in the abluminal pits of the endothelial cells or the basal lamina of vessels in WKY. The number of cationized ferritin particles binding to the endothelial cells of capillaries was decreased in the hippocampus of SHR and SHRSP, while the number decreased in the cerebral cortex of SHRSP compared with those in WKY. However, the cationized ferritin binding was preserved in the endothelial cells of the arterioles with an increased vascular permeability. These findings suggest that the chronic hypertensive state induces BBB dysfunction in the hippocampus at an early stage.

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References

  1. Amano S (1977) Vascular changes in the brain of spontaneously hypertensive rats: hyaline and fibrinoid degeneration. J Pathol 121:119–128

    CAS  PubMed  Google Scholar 

  2. Cavaglia M, Dombrowski SM, Drazba J, Vasanji A, Bokesch PM, Janigro D (2001) Regional variation in brain capillary density and vascular response to ischemia. Brain Res 910:81–93

    Article  CAS  PubMed  Google Scholar 

  3. Cervos-Navarro J, Artigas J, Mrsulja BJ (1983) Morphofunctional aspects of the normal and pathological blood-brain barrier. Acta Neuropathol 8:1-19

    CAS  Google Scholar 

  4. Fredriksson K, Auer RN, Kalimo H, Nordborg C, Olsson Y, Johansson BB (1985) Cerebrovascular lesions in stroke-prone spontaneously hypertensive rats. Acta Neuropathol 68:284–294

    CAS  PubMed  Google Scholar 

  5. Fredriksson K, Kalimo H, Westergren I, Kahrstrom J, Johansson BB (1987) Blood-brain barrier leakage and brain edema in the stroke-prone spontaneously hypertensive rats. Acta Neuropathol 74:259–268

    CAS  PubMed  Google Scholar 

  6. Fredriksson K, Kalimo H, Nordborg C, Olsson Y, Johansson BB (1988) Cyst formation and glial response in the brain lesions of stroke-prone spontaneously hypertensive rats. Acta Neuropathol 76:441–450

    CAS  PubMed  Google Scholar 

  7. Fredriksson K, Nordborg C, Kalimo H, Olsson Y, Johansson BB (1988) Cerebral microangiopathy in stroke-prone spontaneously hypertensive rats. An immunohistochemical and ultrastructural study. Acta Neuropathol 75:241–252

    CAS  PubMed  Google Scholar 

  8. Hachinski VC, Potter P, Merskey H (1987) Leuko-araiosis. Arch Neurol 44:21–23

    CAS  PubMed  Google Scholar 

  9. Hazama F, Amano S, Haebara H, Okamoto K (1975) Changes in vascular permeability in the brain of stroke-prone spontaneously hypertensive rats studied with peroxidase as a tracer. Acta Pathol Jap 25:565–574

    CAS  Google Scholar 

  10. Johansson BB (1977) The cerebrovascular permeability to protein after bicuculline and amphetamine administration in spontaneously hypertensive rats. Acta Neurol Scand 56:397–404

    CAS  PubMed  Google Scholar 

  11. Johansson BB (1980) The blood-brain barrier in acute and chronic hypertension. Adv Exp Med Biol 131:211–226

    CAS  PubMed  Google Scholar 

  12. Knox CA, Yates RD, Chen I-li, Klara PM (1980) Effects of aging on the structural and permeability characteristics of cerebrovasculature in normotensive and hypertensive strains of rats. Acta Neuropathol 51:1-13

    CAS  PubMed  Google Scholar 

  13. Lindner JR, Ismail S, Spotnitz WD, Skyba DM, Jayaweera AR, Kaul S (1998) Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalyx damage. Circulation 98:2187–2194

    CAS  PubMed  Google Scholar 

  14. Mesulam M-M (1978) Tetramethyl benzidine for horseradish peroxidase neurohistochemistry: a non-carcinogenic blue reaction-product with superior sensitivity for visualizing neural afferents and efferents. J Histochem Cytochem 26:106–117

    CAS  PubMed  Google Scholar 

  15. Miyamoto M, Kiyota Y, Yamazaki N, Nagaoka A, Matsuo T, Nagawa Y, Takeda T (1986) Age-related changes in learning and memory in the senescence-accelerated mouse (SAM). Physiol Behav 38:399–406

    Article  CAS  PubMed  Google Scholar 

  16. Mueller SM (1982) The blood-brain barrier in young spontaneously hypertensive rats. Acta Neurol Scand 65:623–628

    CAS  PubMed  Google Scholar 

  17. Nag S (1984) Cerebral endothelial surface charge in hypertension. Acta Neuropathol 63:276–281

    CAS  PubMed  Google Scholar 

  18. Negishi H, Ikeda K, Nara Y, Yamori Y (2001) Increased hydroxyl radicals in the hippocampus of stroke-prone spontaneously hypertensive rats during transient ischemia and recirculation. Neurosci Lett 306:206–208

    Article  CAS  PubMed  Google Scholar 

  19. Ogata J, Fujishima M, Tamaki K, Nakatomi Y, Ishitsuka T, Omae T (1981) Vascular changes underlying cerebral lesions in stroke-prone spontaneously hypertensive rats. Acta Neuropathol 54:183–188

    CAS  PubMed  Google Scholar 

  20. Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jap Circ J 27:282–293

    CAS  PubMed  Google Scholar 

  21. Okamoto K, Yamori Y, Nagaoka A (1974) Establishment of the stroke-prone spontaneously hypertensive rat (SHR). Circ Res 34:143–153

    PubMed  Google Scholar 

  22. Parnetti L, Mari D, Mecocci P, Senin U (1994) Pathogenetic mechanisms in vascular dementia. Int J Clin Lab Res 24:15–22

    CAS  PubMed  Google Scholar 

  23. Reese TS, Karnovsky MJ (1967) Fine structural localization of blood-brain barrier to exogenous peroxidase. J Cell Biol 34:207–217

    CAS  PubMed  Google Scholar 

  24. Ritter S, Dinh TT (1986) Progressive postnatal dilatation of brain ventricles in spontaneously hypertensive rats. Brain Res 370:327–332

    Article  CAS  PubMed  Google Scholar 

  25. Roman GC (1996) From UBOs to Binswanger’s disease: impact of magnetic resonance imaging on vascular dementia research. Stroke 27:1269–1273

    CAS  PubMed  Google Scholar 

  26. Sabbatini M, Strocchi P, Vitaioli L, Amenta F (2000) The hippocampus in spontaneously hypertensive rats: A quantitative microanatomical study. Neuroscience 100:251–258

    Article  CAS  PubMed  Google Scholar 

  27. Sabbtini M, Catalani A, Consoli C, Marletta N, Tomassoni D, Avola R (2002) The hippocampus in spontaneously hypertensive rats: an animal model of vascular dementia. Mech Ageing Dev 123:547–559

    Article  PubMed  Google Scholar 

  28. Schmidt-Kastner R, Szymas J, Hossmann K-A (1990) Immunohistochemical study of glial reaction and serum-protein extravasation in relation to neuronal damage in the rat hippocampus after ischemia. Neuroscience 38:527–540

    Article  CAS  PubMed  Google Scholar 

  29. Shinnou M, Ueno M, Sakamoto H, Ide M (1998) Blood-brain barrier damage in reperfusion following ischemia in the hippocampus of the Mongolian gerbil brain. Acta Neurol Scand 98:406–411

    CAS  PubMed  Google Scholar 

  30. Takeda T, Hosokawa M, Takeshita S, Irino M, Higuchi K, Matsushita T, Tomita Y, Yasuhira K, Hanamoto H, Shimizu K, Ishii M, Yamamuro T (1981) A new murine model of accelerated senescence. Mech Ageing Dev 17:183–194

    Article  CAS  PubMed  Google Scholar 

  31. Thurauf N, Dermietzel R, Kalweit P (1983) Surface charges associated with fenestrated brain capillaries. I. In vitro labeling of anionic sites. J Ultrastruct Res 84:103–110

    CAS  PubMed  Google Scholar 

  32. Ueno M, Akiguchi I, Hosokawa M, Yagi H, Takemura M, Kimura J, Takeda T (1994) Accumulation of blood-borne horseradish peroxidase in medial portions of the mouse hippocampus. Acta Neurol Scand 90:400–404

    CAS  PubMed  Google Scholar 

  33. Ueno M, Akiguchi I, Hosokawa M, Shinnou M, Sakamoto H, Takemura M, Higuchi K (1997) Age-related changes in the brain transfer of blood-borne horseradish peroxidase in the hippocampus of senescence-accelerated mouse. Acta Neuropathol 93:233–240

    Article  CAS  PubMed  Google Scholar 

  34. Ueno M, Akiguchi I, Hosokawa M, Kotani H, Kanenishi K, Sakamoto H (2000) Blood-brain barrier permeability in the periventricular areas of the normal mouse brain. Acta Neuropathol 99:385–392

    Article  CAS  PubMed  Google Scholar 

  35. Ueno M, Sakamoto H, Kanenishi K, Onodera M, Akiguchi I, Hosokawa M (2001) Ultrastructural and permeability features of microvessels in the hippocampus, cerebellum and pons of senescence-accelerated mice (SAM). Neurobiol Aging 22:469–478

    Article  CAS  PubMed  Google Scholar 

  36. Ueno M, Tomimoto H, Akiguchi I, Wakita H, Sakamoto H (2002) Blood-brain barrier disruption in white matter of chronic cerebral hypoperfusion. J Cereb Blood Flow Metab 22:97–104

    Article  PubMed  Google Scholar 

  37. Vorbrodt AW, Lossinsky AS, Dobrogowska DH, Wisniewski HM (1986) Distribution of anionic sites and glycoconjugates on the endothelial surfaces of the developing blood-brain barrier. Dev Brain Res 29:69–79

    Article  CAS  Google Scholar 

  38. Wallin A, Blennow K (1993) Heterogeneity of vascular dementia: mechanisms and subgroups. J Geriatr Psychiatr Neurol 6:177–188

    CAS  Google Scholar 

  39. Wardlaw JM, Sandercock PAG, Dennia MS, Starr J (2003) Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 34:806–812

    Article  CAS  Google Scholar 

  40. Westergaard RD, Brightman MW (1973) Transport of proteins across normal cerebral arterioles. J Comp Neurol 152:17–44

    CAS  PubMed  Google Scholar 

  41. Yamori Y, Horie R, Sato M, Sasagawa S, Okamoto K (1975) Experimental studies on the pathogenesis and prophylaxis of stroke-prone spontaneously hypertensive rats (SHR). (1) Quantitative estimation of cerebrovascular permeability. Jpn Circ J 39:611–615

    CAS  PubMed  Google Scholar 

  42. Yoshida T, Tanaka M, Okamoto K (2002) Immunoglobulin G induces microglial superoxide production. Neurol Res 24(4): 361–364

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to express their appreciation to Ms. C. Ishikawa for technical assistance and to Ms. Y. Fujiwara for editorial assistance. This research was supported by a budget from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, 1750–1 Ikenobe Miki-cho , 761–0793, Kita-gun, Kagawa , Japan

    Masaki Ueno, Haruhiko Sakamoto & Masayuki Onodera

  2. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Hidekazu Tomimoto & Ichiro Akiguchi

  3. Department of Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Cheng-Long Huang

  4. Department of Perinatology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Kenji Kanenishi

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  1. Masaki Ueno
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  2. Haruhiko Sakamoto
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  5. Masayuki Onodera
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Correspondence to Masaki Ueno.

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Ueno, M., Sakamoto, H., Tomimoto, H. et al. Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats. Acta Neuropathol 107, 532–538 (2004). https://doi.org/10.1007/s00401-004-0845-z

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  • DOI: https://doi.org/10.1007/s00401-004-0845-z

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