Pathomorphological changes of capillaries in the cerebral cortex in type 2 diabetes mellitus

Authors

DOI:

https://doi.org/10.14739/2409-2932.2021.3.244360

Keywords:

diabetes mellitus, brain, capillaries, pericytes

Abstract

The aim of the study was to determine microscopic, immunohistochemical, electron microscopic, morphometric parameters of capillaries in the cerebral cortex in deceased patients with type 2 diabetes mellitus (DM) in comparison with the conditional control group and the group of deceased patients with dyscirculatory ischemic encephalopathy.

Materials and methods. Microscopic, immunohistochemical, electron microscopic and morphometric studies of the cerebral cortex capillaries were performed in 3 groups: group I – 20 deceased patients with type 2 DM, group II conditional control (CC) – 20 deceased patients without clinical morphological signs of DM and cerebrovascular pathology, group III – 20 patients with dyscirculatory ischemic encephalopathy (DIEP).

Results. It was found that in type 2 DM, the capillaries in the cerebral cortex lose pericytes due to their apoptosis: the number of pericytes in the cortical capillaries in type 2 DM was statistically significantly lower by 57.14 % compared to CC group and 50.00 % lower compared to DIEP group, the level of caspase-3 expression in the cortical microvessels in type 2 DM was significantly higher by 230.85 % compared with CC group and 81.67 % higher than in DIEP group. According to electron microscopy in type 2 DM, apoptosis of pericytes and single endothelial cells in the cerebral cortex capillaries was determined as well as significant expansion of basement membranes with the accumulation of electron-dense amorphous material and collagen fibrils. According to the results of morphometry, the outer diameter of the cortical capillaries in type 2 DM group was 4.90 % significantly larger, the inner diameter was 9.78 % smaller and the walls were 66.62 % thicker (compared with CC group) due to the accumulation of PAS-positive substances of blood serum and fibrosis, confirmed by 22.96 % greater area of type IV collagen expression in the microvessel walls.

Conclusions. The pathomorphological changes of microvessels identified in deceased patients with type 2 diabetes mellitus are signs of diabetic cerebral microangiopathy.

Author Biographies

V. O. Tumanskyi, Zaporizhzhia State Medical University, Ukraine

MD, PhD, DSc, Professor of the Department of Pathological Anatomy and Forensic Medicine, Vice-Rector for Research

Yu. M. Avramenko, Zaporizhzhia State Medical University, Ukraine

MD, PhD, Assistant of the Department of Pathological Anatomy and Forensic Medicine

References

Lin, X., Xu, Y., Pan, X., Xu, J., Ding, Y., Sun, X., Song, X., Ren, Y., & Shan, P. F. (2020). Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025. Scientific reports, 10(1), 14790. https://doi.org/10.1038/s41598-020-71908-9

World Health Organization. (2021, November 10). Diabetes. https://www.who.int/news-room/fact-sheets/detail/diabetes

Garcia-Serrano, A. M., & Duarte, J. (2020). Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?. Frontiers in neuroscience, 14, 229. https://doi.org/10.3389/fnins.2020.00229

McConnell, H. L., Kersch, C. N., Woltjer, R. L., & Neuwelt, E. A. (2017). The Translational Significance of the Neurovascular Unit. The Journal of biological chemistry, 292(3), 762-770. https://doi.org/10.1074/jbc.R116.760215

Van Sloten, T. T., Sedaghat, S., Carnethon, M. R., Launer, L. J., & Stehouwer, C. (2020). Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. The lancet. Diabetes & endocrinology, 8(4), 325-336. https://doi.org/10.1016/S2213-8587(19)30405-X

Mäe, M. A., Li, T., Bertuzzi, G., Raschperger, E., Vanlandewijck, M., He, L., Nahar, K., Dalheim, A., Hofmann, J. J., Laviña, B., Keller, A., Betsholtz, C., & Genové, G. (2018). Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier. Scientific reports, 8(1), 17462. https://doi.org/10.1038/s41598-018-35576-0

Rom, S., Zuluaga-Ramirez, V., Gajghate, S., Seliga, A., Winfield, M., Heldt, N. A., Kolpakov, M. A., Bashkirova, Y. V., Sabri, A. K., & Persidsky, Y. (2019). Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models. Molecular neurobiology, 56(3), 1883-1896. https://doi.org/10.1007/s12035-018-1195-5

Avtandilov, G. G. (2002). Osnovy kolichestvennoi patologicheskoi anatomii [Fundamentals of quantitative pathological anatomy]. Moscow: Meditsina. [in Russian].

Brown, L. S., Foster, C. G., Courtney, J. M., King, N. E., Howells, D. W., & Sutherland, B. A. (2019). Pericytes and Neurovascular Function in the Healthy and Diseased Brain. Frontiers in cellular neuroscience, 13, 282. https://doi.org/10.3389/fncel.2019.00282

Uemura, M. T., Maki, T., Ihara, M., Lee, V., & Trojanowski, J. Q. (2020). Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia. Frontiers in aging neuroscience, 12, 80. https://doi.org/10.3389/fnagi.2020.00080

Harrell, C. R., Simovic Markovic, B., Fellabaum, C., Arsenijevic, A., Djonov, V., & Volarevic, V. (2018). Molecular mechanisms underlying therapeutic potential of pericytes. Journal of biomedical science, 25(1), 21. https://doi.org/10.1186/s12929-018-0423-7

Geranmayeh, M. H., Rahbarghazi, R., & Farhoudi, M. (2019). Targeting pericytes for neurovascular regeneration. Cell communication and signaling : CCS, 17(1), 26. https://doi.org/10.1186/s12964-019-0340-8

Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., Sun, Y., Raschperger, E., Räsänen, M., Zarb, Y., Mochizuki, N., Keller, A., Lendahl, U., & Betsholtz, C. (2018). A molecular atlas of cell types and zonation in the brain vasculature. Nature, 554(7693), 475-480. https://doi.org/10.1038/nature25739

Hall, C. N., Reynell, C., Gesslein, B., Hamilton, N. B., Mishra, A., Sutherland, B. A., O'Farrell, F. M., Buchan, A. M., Lauritzen, M., & Attwell, D. (2014). Capillary pericytes regulate cerebral blood flow in health and disease. Nature, 508(7494), 55-60. https://doi.org/10.1038/nature13165

Cai, C., Fordsmann, J. C., Jensen, S. H., Gesslein, B., Lønstrup, M., Hald, B. O., Zambach, S. A., Brodin, B., & Lauritzen, M. J. (2018). Stimulation-induced increases in cerebral blood flow and local capillary vasoconstriction depend on conducted vascular responses. Proceedings of the National Academy of Sciences of the United States of America, 115(25), E5796-E5804. https://doi.org/10.1073/pnas.1707702115

Rustenhoven, J., Jansson, D., Smyth, L. C., & Dragunow, M. (2017). Brain Pericytes As Mediators of Neuroinflammation. Trends in pharmacological sciences, 38(3), 291-304. https://doi.org/10.1016/j.tips.2016.12.001

Maric-Bilkan, C., Flynn, E. R., & Chade, A. R. (2012). Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat. American journal of physiology. Renal physiology, 302(3), F308-F315. https://doi.org/10.1152/ajprenal.00421.2011

Price, T. O., Sheibani, N., & Shah, G. N. (2017). Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology. Biochimica et biophysica acta. Molecular basis of disease, 1863(4), 929-935. https://doi.org/10.1016/j.bbadis.2017.01.025

Patrick, P., Price, T. O., Diogo, A. L., Sheibani, N., Banks, W. A., & Shah, G. N. (2015). Topiramate Protects Pericytes from Glucotoxicity: Role for Mitochondrial CA VA in Cerebromicrovascular Disease in Diabetes. Journal of endocrinology and diabetes, 2(2), 1-7. https://doi.org/10.15226/2374-6890/2/2/00123

Hayes K. L. (2019). Pericytes in Type 2 Diabetes. Advances in experimental medicine and biology, 1147, 265-278. https://doi.org/10.1007/978-3-030-16908-4_12

Barber, A. J., Gardner, T. W., & Abcouwer, S. F. (2011). The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy. Investigative ophthalmology & visual science, 52(2), 1156-1163. https://doi.org/10.1167/iovs.10-6293

Sengillo, J. D., Winkler, E. A., Walker, C. T., Sullivan, J. S., Johnson, M., & Zlokovic, B. V. (2013). Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease. Brain pathology, 23(3), 303-310. https://doi.org/10.1111/bpa.12004

Liu, Q., Radwanski, R., Babadjouni, R., Patel, A., Hodis, D. M., Baumbacher, P., Zhao, Z., Zlokovic, B., & Mack, W. J. (2019). Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum. Journal of cerebral blood flow and metabolism, 39(2), 240-250. https://doi.org/10.1177/0271678X17743670

Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019). Blood-Brain Barrier: From Physiology to Disease and Back. Physiological reviews, 99(1), 21-78. https://doi.org/10.1152/physrev.00050.2017

Kisler, K., Nelson, A. R., Rege, S. V., Ramanathan, A., Wang, Y., Ahuja, A., Lazic, D., Tsai, P. S., Zhao, Z., Zhou, Y., Boas, D. A., Sakadžić, S., & Zlokovic, B. V. (2017). Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nature neuroscience, 20(3), 406-416. https://doi.org/10.1038/nn.4489

Persidsky, Y., Hill, J., Zhang, M., Dykstra, H., Winfield, M., Reichenbach, N. L., Potula, R., Mukherjee, A., Ramirez, S. H., & Rom, S. (2016). Dysfunction of brain pericytes in chronic neuroinflammation. Journal of cerebral blood flow and metabolism, 36(4), 794-807. https://doi.org/10.1177/0271678X15606149

Biswas, S., & Chakrabarti, S. (2019). Increased Extracellular Matrix Protein Production in Chronic Diabetic Complications: Implications of Non-Coding RNAs. Non-coding RNA, 5(1), 30. https://doi.org/10.3390/ncrna5010030

Amtul, Z., Yang, J., Lee, T. Y., & Cechetto, D. F. (2019). Pathological Changes in Microvascular Morphology, Density, Size and Responses Following Comorbid Cerebral Injury. Frontiers in aging neuroscience, 11, 47. https://doi.org/10.3389/fnagi.2019.00047

Shavrin, V. O., & Avramenko, Yu. M. (2020). Immunogistokhimicheskaya kharakteristika ekspressii markerov MMP-9 i TIMP-1 v kore golovnogo mozga pri sakharnom diabete 2 tipa [Immunohistochemical characteristics of MMP-9 and TIMP-1 markers expression in the cerebral cortex in diabetes mellitus type 2]. Zaporozhye medical journal, 22(4), 468-472. https://doi.org/10.14739/2310-1210.2020.4.208355

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Published

2021-10-25

How to Cite

1.
Tumanskyi VO, Avramenko YM. Pathomorphological changes of capillaries in the cerebral cortex in type 2 diabetes mellitus. Current issues in pharmacy and medicine: science and practice [Internet]. 2021Oct.25 [cited 2024Apr.24];14(3):354-62. Available from: http://pharmed.zsmu.edu.ua/article/view/244360

Issue

Vol. 14 No. 3 (2021)

Section

Original research

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