Human PhysiologyHuman PhysiologyФизиология человека0131-16463034-6150The Russian Academy of Sciences66408110.31857/S0131164624050076AOHCSIArticlesСтатьиResearch ArticleBlood Proteome Study to Assess the Regulation of Angiogenesis in Cosmonauts After the End of the FlightИсследование протеома крови для оценки регуляции ангиогенеза у космонавтов после завершения полетаGoncharovI. N.ГончаровИ. Н.
Russian Federation
igorgoncharov@gmail.comPastushkovaL. H.ПастушковаЛ. Х.
Russian Federation
igorgoncharov@gmail.comGoncharovaA. G.ГончароваА. Г.
Russian Federation
igorgoncharov@gmail.comKashirinaD. N.КаширинаД. Н.
Russian Federation
daryakudryavtseva@mail.ruLarinaI. M.ЛаринаИ. М.
Russian Federation
igorgoncharov@gmail.comInstitute of Biomedical Problems of the RASИнститут медико-биологических проблем РАН20112024505657525022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0131-1646/article/view/664081

A study of blood samples of 18 cosmonauts who had long flights as members of Russian crews of the International Space Station was performed using the method of quantitative proteomics based on mass spectrometry. The study was focused on elucidation of possible connection of proteome changes under the influence of space flight (SF) factors with the processes of angiogenesis. The analysis was performed with a targeted panel of 125 labeled 13C/15N peptides using chromatography-mass spectrometry with multiple reaction monitoring (LC/MRM-MS). A total of 125 different proteins were quantitatively characterized. Among them, a group of 61 proteins involved in the processes of angiogenesis and its regulation was found. Bioinformatic methods showed that the isolated angiogenesis proteins were participants of 13 biological processes, including lymphangiogenesis. Significant changes of protein level in blood after landing, in relation to preflight samples, were observed in 7 cases. The results have shown that the elimination of gravity (microgravity), space radiation and overloads of the final stage of flight have a combined effect on the processes of angiogenesis, which is manifested by changes in proteomic composition on 1 day after the completion of long-term CP.

Методом количественной протеомики на основе масс-спектрометрии выполнено исследование образцов крови 18 космонавтов, совершивших продолжительные полеты в составе российских экипажей Международной космической станции. Исследование было направлено на выяснение возможной связи изменений протеома, под действием факторов космического полета (КП), с процессами ангиогенеза. Анализ выполнен с использованием целевой панели из 125 меченых 13С/15N пептидов с помощью хромато-масс-спектрометрии с мониторингом множественных реакций (ЖХ/МРМ-МС). Было количественно охарактеризовано 125 различных белков. Среди них обнаружена группа из 61 протеинов, которые участвуют в процессах ангиогенеза и его регуляции. Биоинформатическими методами показано, что выделенные белки ангиогенеза являлись участниками 13 биологических процессов, в том числе лимфангиогенеза. Достоверные изменения уровня белка в крови, после посадки, по отношению к предполетным пробам отмечены в 7 случаях. Результаты показали, что устранение гравитации (микрогравитация), космическая радиация и перегрузки завершающего этапа полета сочетанно воздействуют на процессы ангиогенеза, что проявляется изменениями протеомной композиции на 1-е сут после завершения длительных КП.

angiogenesisbiological processesproteinsspace flightlandingpeculiarities of blood plasma proteomeангиогенезбиологические процессыбелкикосмический полетприземлениеособенности протеома плазмы кровиПравительство Российской ФедерацииGovernment of the Russian FederationFMFR-2024-0032Larina I.M., Buravkova L.B., Grigoriev A.I. [Oxigen-dependent adaptation processes in the human organism in usual living conditions and during space flight] // Aviakosm. Ekol. Med. 2021. V. 55. № 1. P. 5.Ларина И.М., Буравкова Л.Б., Григорьев А.И. Кислород-зависимые адаптационные процессы в организме человека в обычных условиях жизнедеятельности и космическом полете // Авиакосм. экол. мед. 2021. Т. 55. № 1. С. 5Kotovsky E.F., Shimkevich L.L. [Functional morphology under extreme influences]. M.: Nauka, 1971. P. 144.Котовский Е.Ф., Шимкевич Л.Л. Функциональная морфология при экстремальных воздействиях. М.: Наука, 1971. С. 144.Guryeva T.S., Dadasheva O.A., Trukhanov K.A. et al. [Study of the influence of hypomagnetic conditions on the embryogenesis of Japanese quail] // Aviakosm. Ecol. Med. 2013. V. 47. № 4. P. 45.Гурьева Т.С., Дадашева О.А., Труханов К.А. и др. Исследование влияния гипомагнитных условий на эмбриогенез японского перепела // Авиакосм. экол. мед. 2013. Т. 47. № 4. С. 45.Buravkova L.B., Rudimov E.G., Andreeva E.R., Grigoriev A.I. The ICAM-1 expression level determines the susceptibility of human endothelial cells to simulated microgravity // J. Cell. Biochem. 2018. V. 119. № 3. P. 2875.Kuzyk M.A., Parker C.E., Domanski D., Borchers C.H. Development of MRM-based assays for the absolute quantitation of plasma proteins // Methods Mol. Biol. 2013. V. 1023. P. 53.Larina I.M., Percy A.J., Yang J. et al. Protein expression changes caused by spaceflight as measured for 18 Russian cosmonauts // Sci. Rep. 2017. V. 7. № 1. P. 8142.Ivanisenko V.A., Saik O.V., Ivanisenko N.V. et al. ANDSystem: an Associative Network Discovery System for automated literature mining in the field of biology // BMC Syst. Biol. 2015. V. 9. № 2. P. S2.Rho S.S., Ando K., Fukuhara S. Dynamic regulation of vascular permeability by vascular endothelial cadherin-mediated endothelial cell-cell junctions // J. Nippon Med. Sch. 2017. V. 84. № 4. P. 148.Tang M.K.S., Yue P.Y.K., Ip P.P. et al. Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface // Nat. Commun. 2018. V. 9. № 1. P. 2270.Yamamoto K., Takagi Y., Ando K., Fukuhara S. Rap1 small GTPase regulates vascular endothelial-cadherin-mediated endothelial cell-cell junctions and vascular permeability // Biol. Pharm. Bull. 2021. V. 44. № 10. P. 1371.Zou J., Chen Z., Wei X. et al. Cystatin C as a potential therapeutic mediator against Parkinson’s disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units // Cell Death Dis. 2017. V. 8. № 6. P. e2854.Li Z., Wang S., Huo X. et al. Cystatin C expression is promoted by VEGFA blocking, with inhibitory effects on endothelial cell angiogenic functions including proliferation, migration, and chorioallantoic membrane angiogenesis // J. Am. Heart Assoc. 2018. V. 7. № 21. P. e009167.Grimm D., Grosse J., Wehland M. et al. The impact of microgravity on bone in humans // Bone. 2016. V. 87. P. 44.Marchand M., Monnot C., Muller L., Germain S. Extracellular matrix scaffolding in angiogenesis and capillary homeostasis // Semin. Cell Dev. Biol. 2019. V. 89. P. 147.Dittrich A., Grimm D., Sahana J. et al. Key proteins involved in spheroid formation and angiogenesis in endothelial cells after long-term exposure to simulated microgravity // Cell. Physiol. Biochem. 2018. V. 45. № 2. P. 429.Zou L., Cao S., Kang N. et al. Fibronectin induces endothelial cell migration through β1 integrin and Src-dependent phosphorylation of fibroblast growth factor receptor-1 at tyrosines 653/654 and 766 // J. Biol. Chem. 2012. V. 287. № 10. P. 7190.Ambesi A., Klein R.M., Pumiglia K.M., McKeown-Longo P.J. Anastellin, a fragment of the first type III repeat of fibronectin, inhibits extracellular signal-regulated kinase and causes G(1) arrest in human microvessel endothelial cells // Cancer Res. 2005. V. 65. № 1. P. 148.Yi M., Ruoslahti E. A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis // Proc. Natl. Acad. Sci. U.S.A. 2001. V. 98. № 2. P. 620.Klein R.M., Zheng M., Ambesi A. et al. Stimulation of extracellular matrix remodeling by the first type III repeat in fibronectin // J. Cell Sci. 2003. V. 116. Pt. 22. P. 4663.Ambesi A., McKeown-Longo P.J. Anastellin, the angiostatic fibronectin peptide, is a selective inhibitor of lysophospholipid signaling // Mol. Cancer Res. 2009. V. 7. № 2. P. 255.Valenty L.M., Longo C.M., Horzempa C. et al. TLR4 ligands selectively synergize to induce expression of IL-8 // Adv. Wound Care (New Rochelle). 2017. V. 6. № 10. P. 309.Chakravarti S., Magnuson T., Lass J.H. et al. Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican // J. Cell Biol. 1998. V. 141. № 5. P. 1277.Kalamajski S., Oldberg A. Homologous sequence in lumican and fibromodulin leucine-rich repeat 5–7 competes for collagen binding // J. Biol. Chem. 2009. V. 284. №1. P. 534.Schaefer L., Iozzo R.V. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction // J. Biol. Chem. 2008. V. 283. № 31. P. 21305.Niewiarowska J., Brézillon S., Sacewicz-Hofman I. et al. Lumican inhibits angiogenesis by interfering with α2β1 receptor activity and downregulating MMP-14 expression // Thromb. Res. 2011. V. 128. № 5. P. 452.Srikrishna G., Nayak J., Weigle B. et al. Carboxylated N-glycans on RAGE promote S100A12 binding and signaling // J. Cell. Biochem. 2010. V. 110. № 3. P. 645.Lukas A., Neidhart M., Hersberger M. et al. Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes // Eur. Heart J. 2007. V. 28. № 8. P. 941.Geczy C.L., Chung Y.M., Hiroshima Y. Calgranulins may contribute vascular protection in atherogenesis // Circ. J. 2014. V. 78. № 2. P. 271.Viemann D., Strey A., Janning A. et al. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells // Blood. 2005. V. 105. № 7. P. 2955.Harman J.L., Sayers J., Chapman C., Pellet-Many C. Emerging roles for neuropilin-2 in cardiovascular disease // Int. J. Mol. Sci. 2020. V. 21. № 14. P. 5154.Kofler N., Simons M. The expanding role of neuropilin: regulation of transforming growth factor-β and platelet-derived growth factor signaling in the vasculature // Curr. Opin. Hematol. 2016. V. 23. № 3. P. 260.Rizzolio S., Rabinowicz N., Rainero E. et al. Neuropilin-1-dependent regulation of EGF-receptor signaling // Cancer Res. 2012. V. 72. № 22. P. 5801.West D.C., Rees C.G., Duchesne L. et al. Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2 // J. Biol. Chem. 2005. V. 280. № 14. P. 13457.Hu B., Guo P., Bar-Joseph I. et al. Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway // Oncogene. 2007. V. 26. № 38. P. 5577.Jia T., Choi J., Ciccione J. et al. Heteromultivalent targeting of integrin αvβ3 and neuropilin 1 promotes cell survival via the activation of the IGF-1/insulin receptors // Biomaterials. 2018. V. 155. P. 64.Muhl L., Folestad E.B., Gladh H. et al. Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D-PDGFRβ signaling // J. Cell Sci. 2017. V. 130. № 8. P. 1365.Grandclement C., Pallandre J.R., Valmary Degano S. et al. Neuropilin-2 expression promotes TGF-β1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS One. 2011. V. 6. № 7. P. e20444.Xie X., Urabe G., Marcho L. et al. Smad3 regulates neuropilin 2 transcription by binding to its 5’ untranslated region // J. Am. Heart Assoc. 2020. V. 9. № 8. P. e015487.Peng K., Bai Y., Zhu Q. et al. Targeting VEGF-neuropilin interactions: a promising antitumor strategy // Drug Discov. Today. 2019. V. 24. № 2. P. 656.Alexander M.R., Murgai M., Moehle C.W., Owens G.K. Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms // Physiol. Genomics. 2012. V. 44. № 7. P. 417.Gopal U., Pizzo S.V. The endoplasmic reticulum chaperone GRP78 also functions as a cell surface signaling receptor / Cell Surface GRP78, a New Paradigm in Signal Transduction Biology. Elsevier, 2018. P. 9.De Cesari C., Barravecchia I., Pyankova O.V. et al. Hypergravity activates a pro-angiogenic homeostatic response by human capillary endothelial cells // Int. J. Mol. Sci. 2020. V. 21. № 7. P. 2354.Maier J.A., Cialdai F., Monici M., Morbidelli L. The impact of microgravity and hypergravity on endothelial cells // Biomed. Res. Int. 2015. V. 2015. P. 434803.Costa-Almeida R., Carvalho D.T., Ferreira M.J. et al. Effects of hypergravity on the angiogenic potential of endothelial cells // J. R. Soc. Interface. 2016. V. 13. № 124. P. 20160688.Villar C.C., Zhao X.R., Livi C.B., Cochran D.L. Effect of living cellular sheets on the angiogenic potential of human microvascular endothelial cells // J. Periodontol. 2015. V. 86. № 5. P. 703.Barravecchia I., De Cesari C., Forcato M. et al. Microgravity and space radiation inhibit autophagy in human capillary endothelial cells, through either opposite or synergistic effects on specific molecular pathways // Cell. Mol. Life Sci. 2021. V. 79. № 1. P. 28.