L.Kh. Pastushkova1, A.G. Goncharova2, D.N. Kashirina3, V.B. Rusanov4, T.A. Krapivnitskaya5, I.M. Larina6

1–4, 6 Federal State Budgetary Scientific Institution – State Scientific Center of the Russian Federation – Institute of Medical and Biological Problems of the Russian Academy of Sciences (SSC RF – IMBP RAS)
(Moscow, Russia)
5 Federal State Budgetary Educational Institution of Continuous Professional Education Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation (FGBOU DPO RMANPO of the Ministry of Health of Russia) (Moscow, Russia)

Regulation of vascular functions coordinates physiological responses to extreme stressors, which include a complex of space flight factors. Identification of molecular functions, biological processes and signaling pathways carried out with the participation of blood proteome proteins is important for understanding the characteristics of the vascular tone response in astronauts.

Objective – evaluation of the characteristics of vascular tone regulation in astronauts based on blood proteome data.

The participation of five reliably changing proteins in modulating the tonic state of blood vessels by activating or suppressing the synthesis of endothelial-derived regulators was characterized. Molecular associative networks were constructed for these proteins using the ANDsystem bioinformation resource. Practical significance – the obtained data expand knowledge about the signaling pathways and mechanisms involved in the systemic adaptive response of vascular tone to a complex of space flight factors.

Pastushkova L.Kh., Goncharova A.G., Kashirina D.N., Rusanov V.B., Krapivnitskaya T.A., Larina I.M. Regulation of vascular tone in cosmonauts according to blood proteomics data. Biomedicine Radioengineering. 2026. V. 29. № 2. P. 16–26. DOI: https:// doi.org/10.18127/ j15604136-202602-02 (In Russian)

1. Zhang L.F., Yu Z.B., Ma J., Mao Q.W. Peripheral effector mechanism hypothesis on cardiovascular dysfunction after spaceflight. Sheng Li Ke Xue Jin Zhan. 2001. Jan. V. 32(1). P. 13–7. Chinese. PMID: 12545770.
2. Arbeille P., Provost R., Zuj K. Carotid and Femoral Artery Intima-Media Thickness During 6 Months of Spaceflight. Aerosp Med Hum Perform. 2016. May. V. 87(5). P. 449–53. DOI: 10.3357/AMHP.4493.2016. PMID: 27099083.
3. Garrett-Bakelman F.E., Darshi M., Green S.J. et al. The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight. Science. 2019 Apr. V. 12. P. 364(6436):eaau8650. DOI: 10.1126/science.aau8650. PMID: 30975860; PMCID: PMC7580864.
4. Hughson R.L., Robertson A.D., Arbeille P., Shoemaker J.K., Rush J.W., Fraser K.S., Greaves D.K. Increased postflight carotid artery stiffness and inflight insulin resistance resulting from 6-mo spaceflight in male and female astronauts. Am J. Physiol. Heart. Circ. Physiol. 2016. Mar. 1. V. 310(5). P. H628-38. DOI: 10.1152/ajpheart.00802.2015. Epub 2016 Jan 8. PMID: 26747504.
5. Arbeille P., Provost R., Vincent N., Aubert A. Adaptation of the main peripheral artery and vein to long term confinement (Mars 500). PLoS One. 2014. Jan 27. V. 9(1). P. e83063. DOI: 10.1371/journal.pone.0083063. PMID: 24475025; PMCID: PMC3903485.
6. Zwart S.R., Launius R.D., Coen G.K., Morgan J.L., Charles J.B., Smith S.M. Body mass changes during long-duration spaceflight. Aviat Space Environ Med. 2014. Sep. V. 85(9). P. 897–904. DOI: 10.3357/ASEM.3979.2014. PMID: 25197887.
7. Palombo C., Morizzo C., Baluci M., Lucini D., Ricci S., Biolo G., Tortoli P., Kozakova M. Large artery remodeling and dynamics following simulated microgravity by prolonged head-down tilt bed rest in humans. Biomed Res Int. 2015. 2015. P. 342565. DOI: 10.1155/2015/342565. Epub 2015 Jan 13. PMID: 25654096. PMCID: PMC4309028.
8. van Duijnhoven N.T., Green D.J., Felsenberg D., Belavy D.L., Hopman M.T., Thijssen D.H. Impact of bed rest on conduit artery remodeling: effect of exercise countermeasures. Hypertension. 2010. Aug. V. 56(2). P. 240-6. DOI: 10.1161/HYPERTENSIONA HA.110.152868. Epub 2010 Jun 7. PMID: 20530294.
9. Baevsky R.M., Baranov V.M., Funtova I.I., Diedrich A., Pashenko A.V., Chernikova A.G., Drescher J., Jordan J., Tank J. Autonomic cardiovascular and respiratory control during prolonged spaceflights aboard the International Space Station. J. Appl. Physiol. (1985). 2007. Jul. V. 103(1). P. 156-61. DOI: 10.1152/japplphysiol.00137.2007. Epub 2007 Apr 19. PMID: 17446414.
10. Hughson R.L., Helm A., Durante M. Heart in space: effect of the extraterrestrial environment on the cardiovascular system. Nat Rev Cardiol. 2018. Mar. V. 15(3). P. 167–180. DOI: 10.1038/nrcardio.2017.157. Epub 2017 Oct 20. PMID: 29053152.
11. Williams B., Mancia G., Spiering W., Agabiti Rosei E., Azizi M. et al. ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018. Sep 1. V. 39(33). P. 3021–3104. DOI: 10.1093/eurheartj/ehy339. Erratum in: Eur Heart J. 2019. Feb. 1. V. 40(5). P. 475. DOI: 10.1093/eurheartj/ehy686. PMID: 30165516.
12. Jordan J., Limper U., Tank J. Cardiovascular autonomic nervous system responses and orthostatic intolerance in astronauts and their relevance in daily medicine. Neurol Sci. 2022 May. V. 43(5). P. 3039–3051. DOI: 10.1007/s10072-022-05963-7. Epub 2022 Feb 23. PMID: 35194757; PMCID: PMC9018660.
13. Tschakovsky M.E., Matusiak K., Vipond C., McVicar L. Lower limb-localized vascular phenomena explain initial orthostatic hypotension upon standing from squat. Am J Physiol Heart Circ Physiol. 2011. Nov. V. 301(5). P. H2102-12. DOI: 10.1152/ajpheart. 00571.2011. Epub 2011. Aug 19. PMID: 21856921.
14. Norsk P. Adaptation of the cardiovascular system to weightlessness: Surprises, paradoxes and implications for deep space missions. Acta Physiol (Oxf). 2020. Mar. V. 228(3). P. e13434. DOI: 10.1111/apha.13434. Epub 2020 Jan 13. PMID: 31872965.
15. Navasiolava N., Yuan M., Murphy R., Robin A., Coupé M., Wang L., Alameddine A., Gauquelin-Koch G., Gharib C., Li Y., Custaud M.A. Vascular and Microvascular Dysfunction Induced by Microgravity and Its Analogs in Humans: Mechanisms and Countermeasures. Front Physiol. 2020. Aug. 20. V. 11. P. 952. DOI: 10.3389/fphys.2020.00952. PMID: 32973543; PMCID: PMC7468431.
16. Nosovskij A.M., Rusanov V.B., Pastushkova L.H., CHernikova A.G. Fraktal'naya model' analiza dannyh v praktike mediko-biologicheskih issledovanij. Biomedicinskaya radioelektronika. 2019. T. 22. № 5. S. 34–40 (In Russian).
17. Goncharova A.G., Pastushkova L.H., Rusanov V.B., Nosovskij A.M., Kashirina D.N., Goncharov I.N., Chernikova A.G., Brzhozovskij A.G., Larina I.M. Rol' kollagena COL6A1 v modulyacii biomekhanicheskih harakteristik serdechno-sosudistoj sistemy v usloviyah dlitel'noj izolyacii. Biomedicinskaya radioelektronika. 2021. T. 24. № 3. S. 5–17 (In Russian).
18. Foroutan B. Personalized Medicine: A Review with Regard to Biomarkers. J. Bioequiv Availab 2015. V. 7. P. 244–256. DOI:10.4172/jbb.1000248.
19. Ivanisenko T.V., Saik O.V., Demenkov P.S., Ivanisenko N.V., Savostianov A.N., Ivanisenko V.A. ANDDigest: a new web-based module of ANDSystem for the search of knowledge in the scientific literature. BMC Bioinformatics. 2020. Sep. V. 14; 21(Suppl 11). P. 228. DOI: 10.1186/s12859-020-03557-8. PMID: 32921303; PMCID: PMC7488989.
20. Rusanov V., Pastushkova L., Nosovsky A., Luchitskaya E., Kussmaul A., Goncharova A., Kashirina D., Nikolaev E., Orlov O., Larina I. Potential protein markers associated with the functional state of vessels prior to long-term space missions and on the first post-landing day. Acta Astronautica. 2022. V. 195. P. 226–233.
21. Luong T.T.D., Estepa M., Boehme B., Pieske B., Lang F., Eckardt K.U., Voelkl J., Alesutan I. Inhibition of vascular smooth muscle cell calcification by vasorin through interference with TGFβ1 signaling. Cell Signal. 2019. Dec. V. 64. P. 109414. DOI: 10.1016/j.cellsig.2019.109414. Epub 2019 Sep 7. PMID: 31505229.
22. Ikeda Y., Imai Y., Kumagai H., Nosaka T., Morikawa Y., Hisaoka T., Manabe I., Maemura K., Nakaoka T., Imamura T., Miyazono K., Komuro I., Nagai R., Kitamura T. Vasorin, a transforming growth factor beta-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo. Proc Natl Acad Sci USA. 2004. Jul. 20. V. 101(29). P. 10732-7. DOI: 10.1073/pnas.0404117101. Epub 2004 Jul 9. PMID: 15247411; PMCID: PMC490003.
23. Vega J.L., Puebla C., Vásquez R., Farías M., Alarcón J., Pastor-Anglada M., Krause B., Casanello P., Sobrevia L. TGF-beta1 inhibits expression and activity of hENT1 in a nitric oxide-dependent manner in human umbilical vein endothelium. Cardiovasc Res. 2009 Jun. 1. V. 82(3). P. 458–67. DOI: 10.1093/cvr/cvp045. Epub 2009 Feb 4. PMID: 19193655.
24. Shin J.W., Lee J.H., Kim H., Lee D.H., Baek K.H., Sunwoo J.S., Byun J.I., Kim T.J., Jun J.S., Han D., Jung K.Y. Bioinformatic analysis of proteomic data for iron, inflammation, and hypoxic pathways in restless legs syndrome. Sleep Med. 2020. Nov. V. 75. P. 448–455. DOI: 10.1016/j.sleep.2020.09.002. Epub 2020 Sep 13. PMID: 32992101.
25. Asleh R., Levy A.P., Levy N.S., Asleh A., Goldenstein H., Segol I., Gulati R., Lerman L.O., Lerman A. Haptoglobin Phenotype Is Associated With High-Density Lipoprotein-Bound Hemoglobin Content and Coronary Endothelial Dysfunction in Patients With Mild Nonobstructive Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 2019.
26. de la Guía-Galipienso F., Martínez-Ferran M., Vallecillo N., Lavie C.J., Sanchis-Gomar F., Pareja-Galeano H. Vitamin D. and cardiovascular health. Clin Nutr. 2021. May. V. 40(5). P. 2946–2957. DOI: 10.1016/j.clnu.2020.12.025. Epub 2020 Dec 29. PMID: 33397599; PMCID: PMC7770490.
27. Urbonavicius S., Lindholt J.S., Delbosc S., Urbonaviciene G., Henneberg E.W., Vorum H., Meilhac O., Honoré B. Proteins associated with the size and expansion rate of the abdominal aortic aneurysm wall as identified by proteomic analysis. Interact Cardiovasc Thorac Surg. 2010. Oct. V. 11(4). P. 433–41. DOI: 10.1510/icvts.2010.238139. Epub 2010 Jul 30. PMID: 20675398.
28. Priyanka K., Singh S., Gill K. Paraoxonase 3: Structure and Its Role in Pathophysiology of Coronary Artery Disease. Biomolecules. 2019. Dec. 3. V. 9(12). P. 817. DOI: 10.3390/biom9120817. PMID: 31816846; PMCID: PMC6995636.
29. Patel P., Xue Z., King K.S., Parham L., Ford S., Lou Y., Bakshi K.K., Sutton K., Margolis D., Hughes A.R., Spreen W.R. Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir. J. Antimicrob Chemother. 2020. Aug 1. V. 75(8). P. 2240–2248. DOI: 10.1093/jac/dkaa147. PMID: 32361755; PMCID: PMC7366207.
30. Man J., Yu X., Huang H., Zhou W., Xiang C., Huang H., Miele L., Liu Z., Bebek G., Bao S., Yu J.S. Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells. Cell Stem Cell. 2018. Jan 4. V. 22(1). P. 104–118.e6. doi: 10.1016/j.stem.2017.10.005. Epub 2017 Nov 30. PMID: 29198941; PMCID: PMC5756127.
31. Schaer C.A., Deuel J.W., Schildknecht D., Mahmoudi L., Garcia-Rubio I., Owczarek C., Schauer S., Kissner R., Banerjee U., Palmer A.F., Spahn D.R., Irwin D.C., Vallelian F., Buehler P.W., Schaer D.J. Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis. Am J. Respir Crit Care Med. 2016. May 15. V. 193(10). P. 1111–22. DOI: 10.1164/rccm.201510-2058OC. PMID: 26694989; PMCID: PMC4872667.
32. Ramakrishnan L., Pedersen S.L., Toe Q.K., West L.E., Mumby S., Casbolt H., Issitt T., Garfield B., Lawrie A., Wort S.J., Quinlan G.J. The Hepcidin/Ferroportin axis modulates proliferation of pulmonary artery smooth muscle cells. Sci Rep. 2018. Aug 28. V. 8(1). P. 12972. DOI: 10.1038/s41598-018-31095-0. PMID: 30154413; PMCID: PMC6113242.
33. Spagnuolo M.S., Maresca B., La Marca V., Carrizzo A., Veronesi C., Cupidi C., Piccoli T., Maletta R.G., Bruni A.C., Abrescia P., Cigliano L. Haptoglobin interacts with apolipoprotein E and beta-amyloid and influences their crosstalk. ACS Chem Neurosci. 2014. Sep 17. V. 5(9). P. 837–47. DOI: 10.1021/cn500099f. Epub 2014 Aug 1. PMID: 25058565.
34. Rikhi R., Samra G., Arustamyan M., Patel J., Zhou L., Bungo B., Moudgil R. Radiation induced cardiovascular disease: An odyssey of bedside-bench-bedside approach. Life Sci Space Res (Amst). 2020. Nov. V. 27. P. 49–55. DOI: 10.1016/j.lssr.2020.07.005. Epub 2020 Jul 22. PMID: 34756229.
35. Urbonavicius S., Lindholt J.S., Delbosc S., Urbonaviciene G., Henneberg E.W., Vorum H., Meilhac O., Honoré B. Proteins associated with the size and expansion rate of the abdominal aortic aneurysm wall as identified by proteomic analysis. Interact Cardiovasc Thorac Surg. 2010. Oct. V. 11(4). P. 433–41. DOI: 10.1510/icvts.2010.238139. Epub 2010 Jul 30. PMID: 20675398.
36. Saburi E., Tavakol-Afshari J., Biglari S., Mortazavi Y. Is α-N-acetylgalactosaminidase the key to curing cancer? A mini-review and hypothesis. J. BUON. 2017. Nov-Dec. V. 22(6). P. 1372–1377. PMID: 29332325.