Dynamics of development of the systemic inflammatory response and disruption of endothelium-dependent vasodilation of cerebral arteries

Systemic chronic inflammation (SCI) can develop due to diabetes mellitus, coronary artery disease, atherosclerosis, autoimmune diseases, kidney, liver, and lung pathologies, cancer, etc. During the COVID-19 pandemic, there was clear evidence showing that inflammation damages endothelial cells of the vascular wall, leading to impaired microcirculation. Currently, the mechanisms causing pathological changes in the brain amid SCI are still unclear. In this work, we investigated how systemic inflammation affects the vasodilatory function of cerebral arteries. SCI was modeled using the well-established cecal ligation and puncture model, which involves tying off the cecum below the ileocecal valve and puncturing it with a needle. For characterizing the SCI model in animals, we recorded changes in body weight, blood pressure, and analyzed levels of leukocytes, ESR, hematocrit, erythrocyte aggregation in arterial blood, and the number of desquamated endothelial cells in venous blood. The density of the vascular network in the pial membrane and arterial reactivity was studied using in vivo microvascular imaging. The number of vessels per unit area and changes in arterial diameter under the influence of vasoactive substances – aminoguanidine (an inducible NO-synthase inhibitor) and acetylcholine – were measured. From 7 days to 3 months after the onset of SCI, leukocyte levels in rat blood increased by 2.1–1.7 times compared to the control group. The number of desquamated endothelial cells increased by 1.8 times compared to the control. Erythrocyte aggregation rose by an average of 1.3 times. The density of the vascular network in the pial membrane decreased by an average of 1.7 times. The number of constrictions in pial arteries induced by aminoguanidine increased by 1.5 to 3.7 times. The number of arteries that expanded in response to acetylcholine decreased by 1.8 to 4.9 times. Thus, SCI over a period of three months leads to a decrease in the density of the cerebral vascular network and a deterioration in the vasomotor function of endothelial cells in cerebral arteries.

1. Clària J., Arroyo V., Moreau R. Roles of systemic inflammatory and metabolic responses in the pathophysiology of acute-on-chronic liver failure. JHEP Rep. 2023;5(9):100807.

2. Lee K.-S., Yoon S.-H., Hwang I., Ma J.-H., Yang E., Kim R.H., Kim E., Yu J.-W. Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming. J. Neuroinflammation. 2024;21(1):137.

3. Markousis-Mavrogenis G., Pepe A., Lupi A., Apostolou D., Argyriou P., Velitsista S., Vartela V., Quaia E., Mavrogeni S.I. Combined brain-heart MRI identifies cardiac and white matter lesions in patients with systemic lupus erythematosus and/or antiphospholipid syndrome: A pilot study. Eur. J. Radiol. 2024;8(176):111500.

4. Ju Y.-N., Zou Z.-W., Jia B.-W. Ac2-26 activated the AKT1/GSK3β pathway to reduce cerebral neurons pyroptosis and improve cerebral function in rats after cardiopulmonary bypass. BMC Cardiovasc. Disord. 2024;24(1):266.

5. Otsuka S., Matsuzaki R., Kakimoto S., Tachibe Y., Kawatani T., Takada S., Tani A., Nakanishi K., Matsuoka T., Kato Y., Inadome M., Nojima N., Sakakima H., Mizuno K., Matsubara Y., Maruyama I. Ninjin’yoeito reduces fatigue-like conditions by alleviating inflammation of the brain and skeletal muscles in aging mice. PLoS One. 2024;19(5):e0303833.

6. Белобородова Н.В., Острова И.В. Сепсис-ассоциированная энцефалопатия (обзор). Общая реаниматология. 2017;13(5):121–139. https://doi.org/10.15360/1813-9779-2017-5-121-139.

7. Fruekilde S.K., Bailey C.J., Lambertsen K.L., Clausen B.H., Carlsen J., Xu N-L., Drasbek K.R., Gutiérrez-Jiménez E. Disturbed microcirculation and hyperaemic response in a murine model of systemic inflammation. J. Cereb. Blood Flow Metab. 2022;42(12):2303–2317.

8. Lorenzini L., Zanella L., Sannia M., Baldassarro V.A., Moretti M., Cescatti M., Quadalti C., Baldi S., Bartolucci G., Di Gloria L., Ramazzotti M., Clavenzani P., Costanzini A., De Giorgio R., Amedei A., Calzà L., Giardino L. Experimental colitis in young Tg2576 mice accelerates the onset of an Alzheimer’s-like clinical phenotype. Alzheimers Res. Ther. 2024;16(1):116.

9. Li L., Xing M., Wang L., Zhao Y. Maresin 1 alleviates neuroinflammation and cognitive decline in a mouse model of cecal ligation and puncture. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024;49(6):890–902.

10. Zhou Y., Deng Q., Vong C.T., Khan H., Cheang W.S. Oxyresveratrol reduces lipopolysaccharide-induced inflammation and oxidative stress through inactivation of MAPK and NF-κB signaling in brain endothelial cells. Biochem. Biophys. Rep. 2024;40:101823.

11. Yin X.-Y., Tang X.-H., Wang S.-X., Zhao Y.-C., Jia M., Yang J.-J., Ji M.-H., Shen J.-C. HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy. J. Neuroinflammation. 2023;20(1):69.

12. Robledo-Montaña J., Díaz-García C., Martí- nez M., Ambrosio N., Montero E., Marín M.J., Virto L., Muñoz-López M., Herrera D., Sanz M., Leza J.C., García-Bueno B., Figuero E., Martín-Hernández D. Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression. J. Neuroinflammation. 2024;21(1):219.

13. Никифорова Л.Р., Крышень К.Л., Боровкова К.Е. Обзор доклинических моделей сепсиса и септического шока. Лабораторные животные для научных исследований. 2021;4:17–28.

14. Петрищев Н.Н., Беркевич О.А., Власов Т.Д., Волкова Е.В., Зуева Е.Е., Мозговая Е.В. Диагностическая ценность определения дескваминированных эндотелиальных клеток в крови. Клиническая лабораторная диагностика. 2001;1:50–52.

15. Вдовин В.А., Муравьев А.В., Певзнер А.А. Способ определения степени агрегации клеток крови. Ярославский педагогический вестник (Естественные науки). 2012;III(3):151–154.

16. Предтеченский В.Е., Боровская В.М., Марголина Л.Т. Лабораторные методы исследования. Ред. Л.Г. Смирнова, Л.А. Кост. М.: Медгиз. 1950. 804 с.

17. Sokolova I.B. Effects of metabolic disorders and streptozotocin-induced diabetes on cerebral circulation in rats on a hight-fat diet. J. Evol. Biochem. Physiol. 2022;58(3):915–921.

18. Scott J.A., Machoun M., McCormack D.G. Inducible nitric oxide synthase and vascular reactivity in rat thoracic aorta: effect of aminoguanidine. J. Appl. Physiol. 1996;80(1):271–277.

19. Tabernero A., Nadaud S., Corman B., Atkinson J., Capdeville-Atkinson C. Effects of chronic and acute aminoguanidine treatment on tail artery vasomotion in ageing rats. Br. J. Pharmacol. 2000;131(6):1227–1235.

20. Misko T.P., Moore W.M., Kasten T.P., Nickols G.A., Corbett J.A., Tilton R.G., McDaniel M.L., Williamson J.R., Currie M.G. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur. J. Pharmacol. 1993;233(1):119–125.

21. Zamora R., Vodovotz Y., Billiar T.R. Inducible nitric oxide synthase and inflammatory diseases. Mol. Med. 2000;6(5):347–373.

22. Галагудза М.М., Бельский Ю.П., Бельская Н.В. Индуцибельная NO-синтаза как фармакологическая мишень противовоспалительной терапии: надежда не потеряна? Сибирский журнал клинической и экспериментальной медицины. 2023;38(1):13–20.

23. Cinelli M.A., Do H.T., Miley G.P., Silverman R.B. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med. Res. Rev. 2020;40(1):158–189. https://doi.org/10.1002/med.21599.

24. Abalenikhina Y.V., Kosmachevskaya O.V., Topunov A.F. Peroxynitrite: Toxic agent and signaling molecule. Appl. Biochem. Microbiol. 2020;56(6):611–623.

25. Герасимов Л.В., Мороз В.В., Исакова А.А. Микрореологические нарушения при критических состояниях. Общая реаниматология. 2010;1(1):74–78.

26. Vallon M., Chang J., Zhang H., Kuo C.J. Developmental and pathological angiogenesis in the central nervous system. Cell. Mol. Life Sci. 2014;71(18):3489–3506.

27. Evans L.E., Taylor J.L., Smith C.J., Pritchard H.A.T., Greenstein A.S., Allan S.M. Cardiovascular comorbidities, inflammation, and cerebral small vessel disease. Cardiovascular Res. 2021;117:2575–2588.

28. Godo S., Shimokawa H. Endothelial functions. Arterioscler. Thromb. Vasc. Biol. 2017;37(9):e108–e114.

29. Ritson M., Wheeler-Jones C., Stolp H.B. Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target? J. Neuroimmunol. 2024;391:578363.