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Blood flow and endothelial cell phenotype regulation during sprouting angiogenesis

  • Hossein Bazmara
  • M. SoltaniEmail author
  • Mostafa Sefidgar
  • Majid Bazargan
  • Mojtaba Mousavi Naeenian
  • Arman Rahmim
Original Article

Abstract

The role of the endothelial cell environment and shear stress induced by blood flow in phenotype determination and lumen formation has been clearly illustrated in recent studies. In the present work, a model is developed to map environmental and flow induced signals in sprouting angiogenesis to endothelial cell phenotype and lumen formation. To follow the endothelial cell lumen formation, its signaling pathway is incorporated in the present work within the phenotype determination pathway that has been recently utilized to model endothelial cell migration, proliferation, and apoptosis. Moreover, a signaling cascade for shear stress activation of endothelial cells is proposed and used for phenotype determination with activation of blood flow. A Boolean network model is employed to build a hybrid map for the relation between the endothelial cell environmental signals and the endothelial cell fate in sprouting angiogenesis with and without blood flow. This map is very useful in the development of models for sprouting angiogenesis. Moreover, this study shows that inhibition of intracellular signaling molecules, solely or in pairs, blocks angiogenic-signaling pathways and can be used to inhibit angiogenesis.

Keywords

Lumen formation Signal transduction Blood flow Boolean network Shear stress 

Notes

Compliance with Ethical Standards

Conflict of interest

None.

References

  1. 1.
    Ando J, Yamamoto K (2009) Vascular mechanobiology endothelial cell responses to fluid shear stress. Circ J 73:1983–1992CrossRefPubMedGoogle Scholar
  2. 2.
    Ando J, Yamamoto K (2013) Flow detection and calcium signalling in vascular endothelial cells. Cardiovasc Res 99:1–9CrossRefGoogle Scholar
  3. 3.
    Bauer AL, Rohlf T (2012) Investigating the role of cross-talk between chemical and stromal factors in endothelial cell phenotype determination. In: Jackson TL (ed) Modeling tumor vasculature. Springer, New York, pp 89–101Google Scholar
  4. 4.
    Bauer AL, Jackson TL, Jiang Y, Rohlf T (2010) Receptor cross-talk in angiogenesis: mapping environmental cues to cell phenotype using a stochastic, Boolean signaling network model. J Theor Biol 264:838–846CrossRefPubMedGoogle Scholar
  5. 5.
    Bayless KJ, Davis GE (2000) RGD-dependent vacuolation and lumen formation observed during endothelial cell morphogenesis in three-dimensional fibrin matrices involves the αv β3 and α5 β1 integrins. Am J Pathol 156:1673–1683CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bayless KJ, Davis GE (2002) The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices. J Cell Sci 115:1123–1136PubMedGoogle Scholar
  7. 7.
    Bazmara H, Soltani M, Sefidgar M, Bazargan M, Mousavi Naeenian M, Rahmim A (2015) The vital role of blood flow-induced proliferation and migration in capillary network formation in a multiscale model of Angiogenesis. PLoS One 10(6):e0128878. doi: 10.1371/journal.pone.0128878 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bell SE, Mavila A, Salazar R, Bayless KJ, Kanagala S et al (2001) Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. J Cell Sci 114:2755–2773PubMedGoogle Scholar
  9. 9.
    Berk BC (2008) Atheroprotective signaling mechanisms activated by steady laminar flow in endothelial cells. Circulation 117:1082–1089CrossRefPubMedGoogle Scholar
  10. 10.
    Carnevale E, Fogel E, Aplin AC, Gelati M, Howson KM et al (2007) Regulation of postangiogenic neovessel survival by beta1 and beta3 integrins in collagen and fibrin matrices. J Vasc Res 44:40–50CrossRefPubMedGoogle Scholar
  11. 11.
    Chen KD (1999) Mechanotransduction in response to shear stress. J Biol Chem 274:18393–18400CrossRefPubMedGoogle Scholar
  12. 12.
    Chien S, Li S, Shyy YJ (1998) Effects of mechanical forces on signal transduction and gene expression in endothelial cells. Hypertension 31:162–169CrossRefPubMedGoogle Scholar
  13. 13.
    Chun T, Itoh H, Ogawa Y, Tamura N, Takaya K et al (1997) Shear stress augments expression of C-type natriuretic peptide and adrenomedullin. Hypertension 29:1296–1302CrossRefPubMedGoogle Scholar
  14. 14.
    Connolly JO, Simpson N, Hewlett L, Hall A (2002) Rac regulates endothelial morphogenesis and capillary assembly. Mol Biol Cell 13:2474–2485CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cooke JP, Rossitch E, Andon NA, Loscalzo J, Dzau VJ (1991) Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 88:1663–1671CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Davis GE, Bayless KJ (2003) An integrin and Rho GTPase-dependent pinocytic vacuole mechanism controls capillary lumen formation in collagen and fibrin matrices. Microcirculation 10:27–44CrossRefPubMedGoogle Scholar
  17. 17.
    Davis GE, Camarillo CW (1996) An alpha 2 beta 1 integrin-dependent pinocytic mechanism involving intracellular vacuole formation and coalescence regulates capillary lumen and tube formation in three-dimensional collagen matrix. Exp Cell Res 224:39–51CrossRefPubMedGoogle Scholar
  18. 18.
    Davis GE, Senger DR (2005) Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 97:1093–1107CrossRefPubMedGoogle Scholar
  19. 19.
    Davis GE, Pintar Allen KA, Salazar R, Maxwell SA (2001) Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. J Cell Sci 114:917–930PubMedGoogle Scholar
  20. 20.
    Davis GE, Koh W, Stratman AN (2007) Mechanisms controlling human endothelial lumen formation and tube assembly in three-dimensional extracellular matrices. Birth Defects Res C Embryo Today 81:270–285CrossRefPubMedGoogle Scholar
  21. 21.
    Dimmeler S, Haendeler J, Rippmann V, Nehls M, Zeiher A (1996) Shear stress inhibits apoptosis of human endothelial cells. FEBS Lett 399:71–74CrossRefPubMedGoogle Scholar
  22. 22.
    Egginton S, Gerritsen M (2003) Lumen formation: in vivo versus in vitro observations. Microcirculation 10:45–61CrossRefPubMedGoogle Scholar
  23. 23.
    Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–18CrossRefPubMedGoogle Scholar
  24. 24.
    Francis SE, Goh KL, Hodivala-Dilke K, Bader BL, Stark M et al (2002) Central roles of alpha5-beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 22:927–933CrossRefPubMedGoogle Scholar
  25. 25.
    Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A et al (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Holderfield MT, Hughes CCW (2008) Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-beta in vascular morphogenesis. Circ Res 102:637–652CrossRefPubMedGoogle Scholar
  27. 27.
    Hsu P, Li S, Li Y, Usami S, Ratcliffe A et al (2001) Effects of flow patterns on endothelial cell migration into a zone of mechanical denudation. Biochem Biophys Res Commun 285:751–759CrossRefPubMedGoogle Scholar
  28. 28.
    Iden S, Rehder D, August B, Suzuki A, Wolburg-Buchholz K et al (2006) A distinct PAR complex associates physically with VE-cadherin in vertebrate endothelial cells. EMBO Rep 7:1239–1246CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Iruela-Arispe ML, Davis GE (2009) Cellular and molecular mechanisms of vascular lumen formation. Dev Cell 16:222–231CrossRefPubMedGoogle Scholar
  30. 30.
    Ishida T, Peterson T, Kovach N, Berk B (1996) MAP kinase activation by flow in endothelial cells. Role of beta 1 integrins and tyrosine kinases. Circ Res 79:310–316CrossRefPubMedGoogle Scholar
  31. 31.
    Jin Z-G, Ueba H, Tanimoto T, Lungu AO, Frame MD et al (2003) Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ Res 93:354–363CrossRefPubMedGoogle Scholar
  32. 32.
    Jin S, Herzog W, Santoro MM, Mitchell TS, Jungblut B et al (2007) A transgene-assisted genetic screen identifies essential regulators of vascular development in vertebrate embryos. Dev Biol 307:29–42CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Johnson BD, Mather KJ, Wallace JP (2011) Mechanotransduction of shear in the endothelium: basic studies and clinical implications. Vasc Med 16:365–377CrossRefPubMedGoogle Scholar
  34. 34.
    Kaiser D, Freyberg M, Friedl P (1997) Lack of hemodynamic forces triggers apoptosis in vascular endothelial cells. Biochem Biophys Res Commun 231:586–590CrossRefPubMedGoogle Scholar
  35. 35.
    Kamei M, Saunders WB, Bayless KJ, Dye L, Davis GE et al (2006) Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442:453–456CrossRefPubMedGoogle Scholar
  36. 36.
    Kauffman SA (1969) Metabolic stability and epigenesis in randomly constructed genetic nets. J Theor Biol 22:437–467CrossRefPubMedGoogle Scholar
  37. 37.
    Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Koh W, Stratman AN, Sacharidou A, Davis GE (2008) In vitro three dimensional collagen matrix models of endothelial lumen formation during vasculogenesis and angiogenesis. Methods Enzymol 443:83–101CrossRefPubMedGoogle Scholar
  39. 39.
    Koh W, Mahan RD, Davis GE (2008) Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling. J Cell Sci 121:989–1001CrossRefPubMedGoogle Scholar
  40. 40.
    Lee H, Koh G (2003) Shear stress activates Tie2 receptor tyrosine kinase in human endothelial cells. Biochem Biophys Res Commun 304:399–404CrossRefPubMedGoogle Scholar
  41. 41.
    Lehoux S, Tedgui A (1998) Signal transduction of mechanical stresses in the vascular wall. Hypertension 32:338–345CrossRefPubMedGoogle Scholar
  42. 42.
    Levesque M, Nerem R, Sprague E (1990) Vascular endothelial cell proliferation in culture and the influence of flow. Biomaterials 11:702–707CrossRefPubMedGoogle Scholar
  43. 43.
    Li S, Kim M, Hu Y-L, Jalali S, Schlaepfer DD et al (1997) Fluid shear stress activation of focal adhesion kinase linking to mitogen-activated protein kinases. J Biol Chem 272:30455–30462CrossRefPubMedGoogle Scholar
  44. 44.
    Li S, Butler P, Wang Y, Hu Y, Han DC et al (2002) The role of the dynamics of focal adhesion kinase in the mechanotaxis of endothelial cells. Proc Natl Acad Sci USA 99:3546–3551CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Li S, Huang NF, Hsu S (2005) Mechanotransduction in endothelial cell migration. J Cell Biochem 96:1110–1126CrossRefPubMedGoogle Scholar
  46. 46.
    Li Y, Haga J, Chien S (2005) Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech 38:1949–1971CrossRefPubMedGoogle Scholar
  47. 47.
    Li S, Assmann SM, Albert R (2006) Predicting essential components of signal transduction networks: a dynamic model of guard cell abscisic acid signaling. PLoS Biol 4:e312CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Meyer GT, Matthias LJ, Noack L, Vadas MA, Gamble JR (1997) Lumen formation during angiogenesis in vitro involves phagocytic activity, formation and secretion of vacuoles, cell death, and capillary tube remodelling by different populations of endothelial cells. Anat Rec 249:327–340CrossRefPubMedGoogle Scholar
  49. 49.
    Muñoz-Chápuli R, Quesada AR, Angel Medina M (2004) Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci 61:2224–2243CrossRefPubMedGoogle Scholar
  50. 50.
    Ngai CY, Yao X (2010) Vascular responses to shear stress: the involvement of mechanosensors in endothelial cells. Open Circ Vasc J 3:85–94CrossRefGoogle Scholar
  51. 51.
    Nobes CD, Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 18:53–62CrossRefGoogle Scholar
  52. 52.
    O’Brien LE, Yu W, Tang K, Jou TS, Zegers MM et al (2006) Morphological and biochemical analysis of Rac1 in three-dimensional epithelial cell cultures. Methods Enzym 406:676–691CrossRefGoogle Scholar
  53. 53.
    Okahara K, Kambayashi J, Ohnishi T, Fujiwara Y, Kawasaki T et al (1995) Shear stress induces expression of CNP gene in human endothelial cells. FEBS Lett 373:108–110CrossRefPubMedGoogle Scholar
  54. 54.
    Osawa M, Masuda M, Kusano K, Fujiwara K (2002) Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: Is it a mechanoresponsive molecule? J Cell Biol 158:773–785CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Pan S (2009) Molecular mechanisms responsible for the atheroprotective effects of laminar shear stress. Antioxid Redox Signal 11:1669–1682CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Parker L, Schmidt M, Jin S-W, Gray A, Beis D et al (2004) The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature 428:754–758CrossRefPubMedGoogle Scholar
  57. 57.
    Pirraglia C, Jattani R, Myat MM (2006) Rac function in epithelial tube morphogenesis. Dev Biol 290:435–446CrossRefPubMedGoogle Scholar
  58. 58.
    Riaz A (2013) Adhesion dependent signals: cell survival, receptor crosstalk and mechanostimulation. Uppsala UniversityGoogle Scholar
  59. 59.
    Rupp PA, Little CD (2001) Integrins in vascular development. Circ Res 89:566–572CrossRefPubMedGoogle Scholar
  60. 60.
    Sacharidou A, Koh W, Stratman AN, Mayo AM, Fisher KE et al (2010) Endothelial lumen signaling complexes control 3D matrix-specific tubulogenesis through interdependent Cdc42- and MT1-MMP-mediated events. Blood 115:5259–5269CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Sakumura Y, Tsukada Y, Yamamoto N, Ishii S (2005) A molecular model for axon guidance based on crosstalk between rho GTPases. Biophys J 89:812–822CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Sandera EE, ten Kloostera JP, van Delfta S, van der Kammen RA, Collarda JG (1999) Rac downregulates rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol 147:1009–1022CrossRefGoogle Scholar
  63. 63.
    Saunders WB, Bohnsack BL, Faske JB, Anthis NJ, Bayless KJ et al (2006) Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3. J Cell Biol 175:179–191CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Schwarzer C, Teuscher C (2007) RBN toolboxGoogle Scholar
  65. 65.
    Shay-Salit A, Shushy M, Wolfovitz E, Yahav H, Breviario F et al (2002) VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci USA 99:9462–9467CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Shyy YJ, Chien S (2002) Role of integrins in endothelial mechanosensing of shear stress. Circ Res 91:769–775CrossRefPubMedGoogle Scholar
  67. 67.
    Song JW, Munn LL (2011) Fluid forces control endothelial sprouting. Proc Natl Acad Sci USA 108:15342–15347CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Song JW, Bazou D, Munn LL (2012) Anastomosis of endothelial sprouts forms new vessels in a tissue analogue of angiogenesis. Integr Biol (Camb) 4:857–862CrossRefGoogle Scholar
  69. 69.
    Stapor PC, Wang W, Murfee WL, Khismatullin DB (2011) The distribution of fluid shear stresses in capillary sprouts. Cardiovasc Eng Technol 2:124–136CrossRefGoogle Scholar
  70. 70.
    Traub O, Berk BC (1998) Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol 18:677–685CrossRefPubMedGoogle Scholar
  71. 71.
    Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA et al (2005) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431CrossRefPubMedGoogle Scholar
  72. 72.
    Van Leeuwen FN, Kain HET, van der Kammen RA, Michiels F, Kranenburg OW et al (1997) The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. J Cell Biol 139:797–807CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Xia Z, Dickens M, Raingeaud J, Davis R, Greenberg M (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270(5240):1326–1331CrossRefPubMedGoogle Scholar
  74. 74.
    Yu W, Datta A, Leroy P, O’Brien LE, Mak G et al (2005) Beta1-integrin orients epithelial polarity via Rac1 and laminin. Mol Biol Cell 16:433–445CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Federation for Medical and Biological Engineering 2015

Authors and Affiliations

  • Hossein Bazmara
    • 1
  • M. Soltani
    • 1
    • 2
    Email author
  • Mostafa Sefidgar
    • 1
  • Majid Bazargan
    • 1
  • Mojtaba Mousavi Naeenian
    • 1
  • Arman Rahmim
    • 2
  1. 1.Department of Mechanical EngineeringKNT University of TechnologyTehranIran
  2. 2.Department of Radiology and Radiological Science, School of MedicineJohns Hopkins UniversityBaltimoreUSA

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