European Journal of Applied Physiology

, Volume 111, Issue 9, pp 2131–2138 | Cite as

Impact of simulated microgravity on microvascular endothelial cell apoptosis

  • Chun-Yan Kang
  • Lin Zou
  • Ming Yuan
  • Yang Wang
  • Tian-Zhi Li
  • Ye Zhang
  • Jun-Feng Wang
  • Yan Li
  • Xiao-Wei Deng
  • Chang-Ting LiuEmail author
Original Article


Cardiovascular deconditioning is known to occur in astronauts exposed to microgravity. Endothelial dysfunction at microcirculatory sites might contribute to cardiovascular deconditioning induced by weightlessness. Recent studies have reported changes in the morphology and gene expression of endothelial cells exposed to conditions of simulated microgravity. The present study was aimed at examining the effects of microgravity on the apoptosis of microvascular endothelial cells and the mechanism underlying these effects. We simulated a microgravity environment and found that microgravity induced microvascular endothelial cell apoptosis and that this effect was correlated with the downregulation of the PI3K/Akt pathway, increased expression of NF-κB, and depolymerization of F-actin. These findings may provide important insights into the origin of the adverse physiological changes occurring due to exposure to microgravity conditions.


Microgravity Apoptosis Endothelial cell Microvascular PI3K/Akt pathway 



This work was supported by the Defense Medical Fund of China (Grant No. 06Z048) and State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center (Grant No. SMFA09A02). We thank Prof. Ying-Hui Li, Chang-Yong Wang, and Gen-Sheng Han for expert technical assistance.

Conflict of interest

The author(s) declare no conflicts of interest with respect to the authorship and/or publication of this article.


  1. Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326PubMedCrossRefGoogle Scholar
  2. Adams JM, Cory S (2001) Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 26:61–66PubMedCrossRefGoogle Scholar
  3. Aoki M, Nata T, Morishita R, Matsushita H, Nakagami H, Yamamoto K, Yamazaki K, Nakabayashi M, Ogihara T, Kaneda Y (2001) Endothelial apoptosis induced by oxidative stress through activation of NF-κB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension 38:48–55PubMedGoogle Scholar
  4. Asai K, Kudej RK, Shen YT, Yang GP, Takagi G, Kudej AB, Geng YJ, Sato N, Nazareno JB, Vatner DE, Natividad F, Bishop SP, Vatner SF (2000) Peripheral vascular endothelial dysfunction and apoptosis in old monkeys. Arterioscler Thromb Vasc Biol 20:1493–1499PubMedCrossRefGoogle Scholar
  5. Barjaktarovic Z, Nordheim A, Lamkemeyer T, Fladerer C, Madlung J, Hampp R (2007) Time-course of changes in amounts of specific proteins upon exposure to hyper-g, 2-D clinorotation, and 3-D random positioning of Arabidopsis cell cultures. J Exp Bot 58:4357–4363PubMedCrossRefGoogle Scholar
  6. Carlsson SI, Bertilaccio MT, Ballabio E, Maier JA (2003) Endothelial stress by gravitational unloading: effects on cell growth and cytoskeletal organization. Biochim Biophys Acta 1642:173–179PubMedCrossRefGoogle Scholar
  7. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17:590–603PubMedCrossRefGoogle Scholar
  8. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMedGoogle Scholar
  9. Coupe M, Fortrat JO, Larina I, Gauquelin-Koch G, Gharib C, Custaud MA (2009) Cardiovascular deconditioning: from autonomic nervous system to microvascular dysfunctions. Respir Physiol Neurobiol 169:S10–S12PubMedCrossRefGoogle Scholar
  10. Crawford-Young SJ (2006) Effects of microgravity on cell cytoskeleton and embryogenesis. Int J Dev Biol 50:183–191PubMedCrossRefGoogle Scholar
  11. Danese S, Dejana E, Fiocchi C (2007) Immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation. J Immunol 178:6017–6022PubMedGoogle Scholar
  12. Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR (1998) Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 274:2225–2233CrossRefGoogle Scholar
  13. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signaling pathway and cancer. Cancer Treat Rev 30:193–204PubMedCrossRefGoogle Scholar
  14. Gourlay CW, Ayscough KR (2005) A role for actin in aging and apoptosis. Biochem Soc Trans 33:1260–1264PubMedCrossRefGoogle Scholar
  15. Grimm D, Bauer J, Kossmehl P, Shakibaei M, Schoenberger J, Pickenhahn H, Schulze-Tanzil G, Vetter R, Eilles C, Paul M, Cogoli A (2002) Simulated microgravity alters differentiation and increases apoptosis in human follicular thyroid carcinoma cells. FASEB J 16:604–606PubMedGoogle Scholar
  16. Guignandon A, Lafage-Proust MH, Usson Y, Laroche N, Caillot-Augusseau A, Alexandre C, Vico L (2001) Cell cycling determines integrin-mediated adhesion in osteoblastic ROS 17/2.8 cells exposed to space-related conditions. FASEB J 15:2036–2038PubMedGoogle Scholar
  17. Infanger M, Kossmehl P, Shakibaei M, Baatout S, Witzing A, Grosse J, Bauer J, Cogoli A, Faramarzi S, Derradji H, Neefs M, Paul M, Grimm D (2006) Induction of three-dimensional assembly and increase in apoptosis of human endothelial cells by simulated microgravity: impact of vascular endothelial growth factor. Apoptosis 11:749–764PubMedCrossRefGoogle Scholar
  18. Infanger M, Ulbrich C, Baatout S, Wehland M, Kreutz R, Bauer J, Grosse J, Vadrucci S, Cogoli A, Derradji H, Neefs M, Kusters S, Spain M, Paul M, Grimm D (2007) Modeled gravitational unloading induced downregulation of endothelin-1 in human endothelial cells. J Cell Biochem 101:1439–1455PubMedCrossRefGoogle Scholar
  19. Ingber D (1999) How cells (might) sense microgravity. FASEB J 13:S3–S15PubMedGoogle Scholar
  20. Kacena MA, Todd P, Gerstenfeld LC, Landis WJ (2002) Experiments with osteoblasts cultured under varying orientations with respect to the gravity vector. Cytotechnology 39:147–154PubMedCrossRefGoogle Scholar
  21. Kossmehl P, Schonberger J, Shakibaei M, Faramarzi S, Kurth E, Habighorst B, von Bauer R, Wehland M, Kreutz R, Infanger M, Schulze-Tanzil G, Paul M, Grimm D (2005) Increase of fibronectin and osteopontin in porcine hearts following ischemia and reperfusion. J Mol Med 83:626–637PubMedCrossRefGoogle Scholar
  22. Lang I, Pabst MA, Hiden U, Blaschitz A, Dohr G, Hahn T, Desoye G (2003) Heterogeneity of microvascular endothelial cells isolated from human term placenta and macrovascular umbilical vein endothelial cells. Eur J Cell Biol 82:163–173PubMedCrossRefGoogle Scholar
  23. Li X, Liu CT, Zhou H (2009) The influence of leptin on the activity of lung lymphocytes under simulated microgravity. Eur J Appl Physiol 107:335–344PubMedCrossRefGoogle Scholar
  24. Matsushita H, Morishita R, Nata T, Aoki M, Nakagami H, Taniyama Y, Yamamoto K, Higaki J, Yasufumi K, Ogihara T (2000) Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-κB)-mediated Bcl-2 suppression: in vivo evidence of the importance of NF-κB in endothelial cell regulation. Circ Res 86:974–981PubMedGoogle Scholar
  25. Morbidelli L, Monici M, Marziliano N, Cogoli A, Fusi F, Waltenberger J, Ziche M (2005) Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals. Biochem Biophys Res Commun 334:491–499PubMedCrossRefGoogle Scholar
  26. Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal 14:381–395PubMedCrossRefGoogle Scholar
  27. Qin ZH, Wang Y, Nakai M, Chase TN (1998) Nuclear factor-kB contributes to excitotoxin-induced apoptosis in rat striatum. Mol Pharmacol 53:33–42PubMedGoogle Scholar
  28. Ribatti D, Nico B, Vacca L, Roncali L, Dammacco F (2002) Endothelial cell heterogeneity and organ specificity. J Hematother Stem Cell Res 11:81–90PubMedCrossRefGoogle Scholar
  29. Shah SA, Potter MW, Hedeshian MH, Kim RD, Chari RS, Callery MP (2001) PI-3′Kinase and NF-κB cross-signaling in human pancreatic cancer cells. J Gastroint Surg 5:603–612CrossRefGoogle Scholar
  30. Spehlmann ME, Eckmann L (2009) Nuclear factor-kappa B in intestinal protection and destruction. Curr Opin Gastroenterol 25:92–99PubMedCrossRefGoogle Scholar
  31. Turner RT (2000) Physiology of a microgravity environment invited review: what do we know about the effects of spaceflight on bone? J Appl Physiol 89:840–847PubMedGoogle Scholar
  32. Uva BM, Masini MA, Sturla M, Prato P, Passalacqua M, Giuliani M, Tagliafierro G, Strollo F (2002) Clinorotation-induced weightlessness influences the cytoskeleton of glial cells in culture. Brain Res 934:132–139PubMedCrossRefGoogle Scholar
  33. Vassy J, Portet S, Beil M, Millot G, Fauvel-Lafève F, Karniguian A, Gasset G, Irinopoulou T, Calvo F, Rigaut JP, Schoevaert D (2001) The effect of weightlessness on cytoskeleton architecture and proliferation of human breast cancer cell line MCF-7. FASEB J 15:1104–1106PubMedGoogle Scholar
  34. Versari S, Villa A, Bradamante S, Maier JA (2007) Alterations of the actin cytoskeleton and increased nitric oxide synthesis are common features in human primary endothelial cell response to changes in gravity. Biochim Biophys Acta 1773:1645–1652PubMedCrossRefGoogle Scholar
  35. Wang J, Zhang J, Bai S, Wang G, Mu L, Sun B, Wang D, Kong Q, Liu Y, Yao X, Xu Y, Li H (2009a) Simulated microgravity promotes cellular senescence via oxidant stress in rat PC12 cells. Neurochem Int 55:710–716PubMedCrossRefGoogle Scholar
  36. Wang M, Wang Y, Weil B, Abarbanell A, Herrmann J, Tan J, Kelly M, Meldrum DR (2009b) Estrogen receptor beta mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. Am J Physiol Regul Integr Comp Physiol 296:R972–R978PubMedCrossRefGoogle Scholar
  37. Wang YC, Zhang S, Du TY, Wang B, Sun XQ (2009c) Clinorotation upregulates inducible nitric oxide synthase by inhibiting AP-1 activation in human umbilical vein endothelial cells. J Cell Biochem 107:357–363PubMedCrossRefGoogle Scholar
  38. West JB (2000) Physiology of a microgravity environment historical perspectives: physiology in microgravity. J Appl Physiol 89:179–384Google Scholar
  39. Zhao L, Lee JY, Hwang DH (2008) The phosphatidylinositol 3-kinase/Akt pathway negatively regulates Nod2-mediated NF-κB pathway. Biochem Pharmacol 75:1515–1525PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Chun-Yan Kang
    • 1
  • Lin Zou
    • 1
  • Ming Yuan
    • 2
  • Yang Wang
    • 1
  • Tian-Zhi Li
    • 1
  • Ye Zhang
    • 1
  • Jun-Feng Wang
    • 1
  • Yan Li
    • 3
  • Xiao-Wei Deng
    • 4
  • Chang-Ting Liu
    • 1
    Email author
  1. 1.Nanlou Respiratory Diseases DepartmentChinese PLA General HospitalBeijingPeople’s Republic of China
  2. 2.The State Key Laboratory of Space Medicine Fundamentals and ApplicationChina Astronaut Research and Training CenterBeijingPeople’s Republic of China
  3. 3.Department of Respiratory DiseasesAffiliated Hospital of the Academy of Military Medical ScienceBeijingPeople’s Republic of China
  4. 4.Exclusive Medical Care Centre, General Hospital of Chinese People of Armed Police ForcesBeijingPeople’s Republic of China

Personalised recommendations