Skip to main content
Log in

Intussusceptive angiogenesis: expansion and remodeling of microvascular networks

  • Review Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Intussusceptive angiogenesis is a dynamic intravascular process capable of dramatically modifying the structure of the microcirculation. The distinctive structural feature of intussusceptive angiogenesis is the intussusceptive pillar—a cylindrical microstructure that spans the lumen of small vessels and capillaries. The extension of the intussusceptive pillar appears to be a mechanism for pruning redundant or inefficient vessels, modifying the branch angle of bifurcating vessels and duplicating existing vessels. Despite the biological importance and therapeutic potential, intussusceptive angiogenesis remains a mystery, in part, because it is an intravascular process that is unseen by conventional light microscopy. Here, we review several fundamental questions in the context of our current understanding of both intussusceptive and sprouting angiogenesis. (1) What are the physiologic signals that trigger pillar formation? (2) What endothelial and blood flow conditions specify pillar location? (3) How do pillars respond to the mechanical influence of blood flow? (4) What biological influences contribute to pillar extension? The answers to these questions are likely to provide important insights into the structure and function of microvascular networks.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CAM:

Chick chorioallantoic membrane

EPC:

Endothelial progenitor cell

GFP:

Green fluorescent protein

SEM:

Scanning electron microscopy

TEM:

Transmission electron microscopy

References

  1. Eming SA, Brachvogel B, Odorisio T, Koch M (2007) Regulation of angiogenesis: wound healing as a model. Prog Histochem Cytochem 42:115–170

    Article  CAS  PubMed  Google Scholar 

  2. Song JJ, Ott HC (2011) Organ engineering based on decellularized matrix scaffolds. Trends Mol Med 17:424–432

    Article  CAS  PubMed  Google Scholar 

  3. Zhao Y, Bao Q, Renner A, Camaj P, Eichhorn M, Ischenko I, Angele M, Kleespies A, Jauch KW, Bruns C (2011) Cancer stem cells and angiogenesis. Int J Dev Biol 55:477–482

    Article  CAS  PubMed  Google Scholar 

  4. Clark ER (1918) Studies on the growth of blood-vessels in the tail of the frog larva—by observation and experiment on the living animal. Am J Anat 23:37–88

    Article  Google Scholar 

  5. Schulte HW (1914) Early stages of vasculogenesis in the cat (Felis domestica) with especial reference to the mesenchymal origin of endothelium. The Wistar Institute of Anatomy and Biology

  6. Clark ER, Clark EL (1940) Microscopic observations on the extra-endothelial cells of living mammalian blood vessels. Am J Anat 66:1–49

    Article  Google Scholar 

  7. Caduff JH, Fischer LC, Burri PH (1986) Scanning electron microscope study of the developing microvasculature in the postnatal rat lung. Anat Rec 216:154–164

    Article  CAS  PubMed  Google Scholar 

  8. Ogawa Y (1977) On the fine structural changes of the microvascular beds in skeletal muscle. J Yokohama City Univ Sec Sport Sci Med 6:1–19

    Google Scholar 

  9. Appell H-J (1980) Morphological studies on skeletal muscle under conditions of high altitude training. Int J Sports Med 1:103–109

    Article  Google Scholar 

  10. Hughes GM, Morgan M (1973) Structure of fish gills in relation to their respiratory function. Biol Rev Camb Philos Soc 48:419–475

    Article  Google Scholar 

  11. Olson KR, Dewar H, Graham JB, Brill RW (2003) Vascular anatomy of the gills in a high energy demand teleost, the skipjack tuna (Katsuwonus pelamis). J Exp Zool 297A:17–31

    Article  Google Scholar 

  12. Mongera A, Singh AP, Levesque MP, Chen YY, Konstantinidis P, Nusslein-Volhard C (2013) Genetic lineage labeling in zebrafish uncovers novel neural crest contributions to the head, including gill pillar cells. Development 140:916–925

    Article  CAS  PubMed  Google Scholar 

  13. Makanya AN, Hlushchuk R, Djonov VG (2009) Intussusceptive angiogenesis and its role in vascular morphogenesis, patterning, and remodeling. Angiogenesis 12:113–123

    Article  CAS  PubMed  Google Scholar 

  14. Konerding MA, Turhan A, Ravnic DJ, Lin M, Fuchs C, Secomb TW, Tsuda A, Mentzer SJ (2010) Inflammation-induced intussusceptive angiogenesis in murine colitis. Anat Rec 293:849–857

    Article  Google Scholar 

  15. Ribatti D, Djonov V (2012) Intussusceptive microvascular growth in tumors. Cancer Lett 316:126–131

    Article  CAS  PubMed  Google Scholar 

  16. Egginton S, Zhou AL, Brown MD, Hudlicka O (2001) Unorthodox angiogenesis in skeletal muscle. Cardiovasc Res 49:634–646

    Article  CAS  PubMed  Google Scholar 

  17. Konerding MA (1991) Scanning electron microscopy of corrosion casting in medicine. Scanning Microsc 5:851–865

    CAS  PubMed  Google Scholar 

  18. Lametschwandtner A, Aharinejad S (1997) Scanning electron microscopy/corrosion casting technique in biological and medical research. State of the art and perspectives. In: Recent advances in microscopy of cells, tissues and organs. Antonio Delfino, Rome. pp 51–58

  19. Gottlieb AI, Langille BL, Wong MK, Kim DW (1991) Structure and function of the endothelial cytoskeleton. Lab Invest 65:123–137

    CAS  PubMed  Google Scholar 

  20. Malek AM, Izumo S (1996) Mechanism of endothelial cell shape change and cytoskeletal remodeling in response to fluid shear stress. J Cell Sci 109(Pt 4):713–726

    CAS  PubMed  Google Scholar 

  21. Galbraith CG, Skalak R, Chien S (1998) Shear stress induces spatial reorganization of the endothelial cell cytoskeleton. Cell Motil Cytoskelet 40:317–330

    Article  CAS  Google Scholar 

  22. Barbee KA, Davies PF, Lal R (1994) Shear stress-induced reorganization of the surface topography of living endothelial cells imaged by atomic force microscopy. Circ Res 74:163–171

    Article  CAS  PubMed  Google Scholar 

  23. Lee GS, Filipovic N, Lin M, Gibney BC, Simpson DC, Konerding MA, Tsuda A, Mentzer SJ (2011) Intravascular pillars and pruning in the extraembryonic vessels of chick embryos. Dev Dyn 240:1335–1343

    Article  PubMed Central  PubMed  Google Scholar 

  24. Schraufnagel DE, Schmid A (1988) Microvascular casting of the lung: effects of various fixation protocols. J Electron Microsc Tech 8:185–191

    Article  CAS  PubMed  Google Scholar 

  25. Nico B, Crivellato E, Ribatti D (2007) The importance of electron microscopy in the study of capillary endothelial cells: an historical review. Endothelium 14:257–264

    Article  PubMed  Google Scholar 

  26. Burri PH, Tarek MR (1990) A novel mechanism of capillary growth in the rat pulmonary microcirculation. Anat Rec 228:35–45

    Article  CAS  PubMed  Google Scholar 

  27. Williams JL, Cartland D, Rudge JS, Egginton S (2006) VEGF trap abolishes shear stress- and overload-dependent angiogenesis in skeletal muscle. Microcirculation 13:499–509

    Article  CAS  PubMed  Google Scholar 

  28. Paku S, Dezso K, Bugyik E, Tovari J, Timar J, Nagy P, Laszlo V, Klepetko W, Dome B (2011) A new mechanism for pillar formation during tumor-induced intussusceptive angiogenesis. Am J Pathol 179:1573–1585

    Article  PubMed Central  PubMed  Google Scholar 

  29. Eming SA, Hubbell JA (2011) Extracellular matrix in angiogenesis: dynamic structures with translational potential. Exp Dermatol 20:605–613

    Article  PubMed  Google Scholar 

  30. Brown MD, Hudlicka O (2003) Modulation of physiological angiogenesis in skeletal muscle by mechanical forces: involvement of VEGF and metalloproteinases. Angiogenesis 6:1–14

    Article  CAS  PubMed  Google Scholar 

  31. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Hansen-Smith FM, Hudlicka O, Egginton S (1996) In vivo angiogenesis in adult rat skeletal muscle: early changes in capillary network architecture and ultrastructure. Cell Tissue Res 286:123–136

    Article  CAS  PubMed  Google Scholar 

  33. Djonov V, Baum O, Burri PH (2003) Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res 314:107–117

    Article  PubMed  Google Scholar 

  34. Makanya AN, Stauffer D, Ribatti D, Burri PH, Djonov V (2005) Microvascular growth, development, and remodeling in the embryonic avian kidney: the interplay between sprouting and intussusceptive angiogenic mechanisms. J Electron Microsc Tech 66:275–288

    CAS  Google Scholar 

  35. Eilken HM, Adams RH (2010) Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 22:617–625

    Article  CAS  PubMed  Google Scholar 

  36. Wacker A, Gerhardt H (2011) Endothelial development taking shape. Curr Opin Cell Biol 23:676–685

    CAS  PubMed  Google Scholar 

  37. Lee CY, Bautch VL (2011) Ups and downs of guided vessel sprouting: the role of polarity. Physiology 26:326–333

    Article  CAS  PubMed  Google Scholar 

  38. Iruela-Arispe ML, Davis GE (2009) Cellular and molecular mechanisms of vascular lumen formation. Dev Cell 16:222–231

    Article  CAS  PubMed  Google Scholar 

  39. Ackermann M, Tsuda A, Secomb TW, Mentzer SJ, Konerding MA (2013) Intussusceptive remodeling of vascular branch angles in chemically-induced murine colitis. Microvasc Res 87:75–82

    Article  PubMed Central  PubMed  Google Scholar 

  40. Lee GS, Filipovic N, Miele LF, Simpson DC, Lin M, Konerding MA, Tsuda A, Mentzer SJ (2010) Blood flow shapes intravascular pillar geometry in the chick chorioallantoic membrane. J Angiogenes Res 2:11–20

    Article  PubMed Central  PubMed  Google Scholar 

  41. Filipovic N, Tsuda A, Lee GS, Miele L, Lin M, Konerding MA, Mentzer SJ (2009) Computational flow dynamics in a geometric model of intussusceptive angiogenesis. Microvasc Res 78:286–293

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Hudlicka O, Brown MD, Egginton S (2004) Microcirculation in muscle. Myology: basic and clinical. McGraw-Hill, London, pp 511–533

    Google Scholar 

  43. Egginton S, Hudlicka O, Brown MD, Walter H, Weiss JB, Bate A (1998) Capillary growth in relation to blood flow and performance in overloaded rat skeletal muscle. J Appl Physiol 85:2025–2032

    CAS  PubMed  Google Scholar 

  44. Hudlicka O, Brown M, Egginton S (1992) Angiogenesis in skeletal and cardiac-muscle. Physiol Rev 72:369–417

    CAS  PubMed  Google Scholar 

  45. Green DJ, Maiorana AJ, Cable NT (2008) Point: counterpoint: exercise training does/does not induce vascular adaptations beyond the active muscle beds. J Appl Physiol 105:1002–1004

    Article  PubMed  Google Scholar 

  46. Milkiewicz M, Hudlicka O, Brown MD, Silgram H (2005) Nitric oxide, VEGF, and VEGFR-2: interactions in activity-induced angiogenesis in rat skeletal muscle. Am J Physiol Heart Circ Physiol 289:H336–H343

    Article  CAS  PubMed  Google Scholar 

  47. Hudlicka O, Brown MD (2009) Adaptation of skeletal muscle microvasculature to increased or decreased blood flow: role of shear stress, nitric oxide and vascular endothelial growth factor. J Vasc Res 46:504–512

    Article  CAS  PubMed  Google Scholar 

  48. Tornling G, Adolfsson J, Unge G, Ljungqvist A (1980) Capillary neoformation in skeletal-muscle of dipyridamole-treated rats. Arzneimittel-Forschung 30–1:791–792

    Google Scholar 

  49. Hudlicka O, Komarek J, Wright AJA (1981) The effect of a xanthine derivative, 1-(5′-oxohexyl)-3-methyl-7-propylxanthine (hwa-285), on heart performance and regional blood-flow in dogs and rabbits. Br J Pharmacol 72:723–730

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Milkiewicz M, Brown MD, Egginton S, Hudlicka O (2001) Association between shear stress, angiogenesis, and VEGF in skeletal muscles in vivo. Microcirculation 8:229–241

    Article  CAS  PubMed  Google Scholar 

  51. Hudlicka O, Graciotti L, Fulgenzi G, Brown MD, Egginton S, Milkiewicz M, Granata AL (2003) The effect of chronic skeletal muscle stimulation on capillary growth in the rat: are sensory nerve fibres involved? J Physiol Lond 546:813–822

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Rivilis I, Milkiewicz M, Boyd P, Goldstein J, Brown MD, Egginton S, Hansen FM, Hudlicka O, Haas TL (2002) Differential involvement of MMP-2 and VEGF during muscle stretch-versus shear stress-induced angiogenesis. Am J Physiol Heart Circ Physiol 283:H1430–H1438

    CAS  PubMed  Google Scholar 

  53. Resnick N, Yahav H, Schubert S, Wolfovitz E, Shay A (2000) Signalling pathways in vascular endothelium activated by shear stress: relevance to atherosclerosis. Curr Opin Lipidol 11:167–177

    Article  CAS  PubMed  Google Scholar 

  54. Ando J, Yamamoto K (2011) Effects of shear stress and stretch on endothelial function. Antioxid Redox Signal 15:1389–1403

    Article  CAS  PubMed  Google Scholar 

  55. Baxter LT, Jain RK (1988) Vascular-permeability and interstitial diffusion in superfused tissues—a two-dimensional model. Microvasc Res 36:108–115

    Article  CAS  PubMed  Google Scholar 

  56. Ravnic DJ, Konerding MA, Huss HT, Wolloscheck T, Pratt JP, Mentzer SJ (2007) Murine microvideo endoscopy of the colonic microcirculation. J Surg Res 142:97–103

    Article  PubMed Central  PubMed  Google Scholar 

  57. Ravnic DJ, Konerding MA, Tsuda A, Jiang X, Huss HT, Pratt JP, Mentzer SJ (2007) Structural adaptations in the murine colon microcirculation associated with hapten-induced inflammation. Gut 56:518–523

    Article  PubMed Central  PubMed  Google Scholar 

  58. Turhan A, Konerding MA, Tsuda A, Ravnic DJ, Hanidizar D, Lin MY, Mentzer SJ (2007) Bridging mucosal vessels associated with rhythmically oscillating blood flow in murine colitis. Anat Rec 291:74–92

    Article  Google Scholar 

  59. Tsuda A, Turhan A, Konerding MA, Ravnic DJ, Hanidziar D, Lin M, Mentzer SJ (2009) Bimodal oscillation frequencies of blood flow in the inflammatory colon microcirculation. Anat Rec 292:65–72

    Article  Google Scholar 

  60. Miele LF, Turhan A, Lee GS, Lin M, Ravnic DJ, Tsuda A, Konerding MA, Mentzer SJ (2009) Blood flow patterns spatially associated with platelet aggregates in murine colitis. Anat Rec 292:1143–1153

    Article  CAS  Google Scholar 

  61. Stump MM, Jordan GL Jr, Debakey ME, Halpert B (1963) Endothelium grown from circulating blood on isolated intravascular Dacron hub. Am J Pathol 43:361–367

    CAS  PubMed Central  PubMed  Google Scholar 

  62. O’Neal RM, Jordan GL Jr, Rabin ER, Debakey ME, Halpert B (1964) Cells grown on isolated intravascular Dacron hub; an electron microscopic study. Exp Mol Pathol 90:403–412

    Article  PubMed  Google Scholar 

  63. Gibney B, Chamoto K, Lee GS, Simpson DC, Miele L, Tsuda A, Konerding MA, Wagers A, Mentzer SJ (2012) Cross-circulation and cell distribution kinetics in parabiotic mice. J Cell Physiol 227:821–828

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Bunster E, Meyer RK (1933) An improved method of parabiosis. Anat Rec 57:339–343

    Article  Google Scholar 

  65. Swenson ES, Price JG, Brazelton T, Krause DS (2007) Limitations of green fluorescent protein as a cell lineage marker. Stem Cells 25:2593–2600

    Article  CAS  PubMed  Google Scholar 

  66. Chamoto K, Gibney BC, Lee GS, Lin M, Simpson DC, Voswinckel R, Konerding MA, Tsuda A, Mentzer SJ (2012) CD34+ progenitor to endothelial cell transition in post-pneumonectomy angiogenesis. Am J Respir Cell Mol Biol 46:283–289

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Chamoto K, Gibney BC, Lee GS, Ackermann M, Konerding MA, Tsuda A, Mentzer SJ (2013) Migration of CD11b+ accessory cells during murine lung regeneration. Stem Cell Res 10:267–277

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven J. Mentzer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mentzer, S.J., Konerding, M.A. Intussusceptive angiogenesis: expansion and remodeling of microvascular networks. Angiogenesis 17, 499–509 (2014). https://doi.org/10.1007/s10456-014-9428-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-014-9428-3

Keywords

Navigation