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The shunt problem: control of functional shunting in normal and tumour vasculature

Nature Reviews Cancer volume 10, pages 587–593 (2010)Cite this article

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Abstract

Networks of blood vessels in normal and tumour tissues have heterogeneous structures, with widely varying blood flow pathway lengths. To achieve efficient blood flow distribution, mechanisms for the structural adaptation of vessel diameters must be able to inhibit the formation of functional shunts (whereby short pathways become enlarged and flow bypasses long pathways). Such adaptation requires information about tissue metabolic status to be communicated upstream to feeding vessels, through conducted responses. We propose that impaired vascular communication in tumour microvascular networks, leading to functional shunting, is a primary cause of dysfunctional microcirculation and local hypoxia in cancer. We suggest that anti-angiogenic treatment of tumours may restore vascular communication and thereby improve or normalize flow distribution in tumour vasculature.

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Figure 1: Microvascular networks.
Figure 2: The shunt problem.
Figure 3: Mechanisms for avoidance of the shunt problem.
Figure 4: Structure and functional characteristics of a normal microvascular network.
Figure 5: Effects of altered information transfer on predicted network function.
Figure 6: Simulated tumour-like structural adaptation.

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References

  1. Duling, B. R. & Damon, D. H. An examination of the measurement of flow heterogeneity in striated muscle. Circ. Res. 60, 1–13 (1987).

    Article  CAS  Google Scholar 

  2. Decking, U. K. Spatial heterogeneity in the heart: recent insights and open questions. News Physiol. Sci. 17, 246–250 (2002).

    PubMed  Google Scholar 

  3. Pries, A. R., Secomb, T. W. & Gaehtgens, P. Structure and hemodynamics of microvascular networks: heterogeneity and correlations. Am. J. Physiol. 269, H1713–H1722 (1995).

    CAS  PubMed  Google Scholar 

  4. Pries, A. R. & Secomb, T. W. Origins of heterogeneity in tissue perfusion and metabolism. Cardiovasc. Res. 81, 328–335 (2009).

    Article  CAS  Google Scholar 

  5. Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    Article  CAS  Google Scholar 

  6. Gewirtz, H., Tawakol, A. & Bacharach, S. L. Heterogeneity of myocardial blood flow and metabolism: review of physiologic principles and implications for radionuclide imaging of the heart. J. Nucl. Cardiol. 9, 534–541 (2002).

    Article  Google Scholar 

  7. Bassingthwaighte, J. B., King, R. B. & Roger, S. A. Fractal nature of regional myocardial blood flow heterogeneity. Circ. Res. 65, 578–590 (1989).

    Article  CAS  Google Scholar 

  8. Jain, R. K. Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nature Rev. Cancer 8, 309–316 (2008).

    Article  CAS  Google Scholar 

  9. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    CAS  Google Scholar 

  10. Horsman, M. R. & Siemann, D. W. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies. Cancer Res. 66, 11520–11539 (2006).

    Article  CAS  Google Scholar 

  11. Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer 8, 592–603 (2008).

    Article  CAS  Google Scholar 

  12. Martinez-Lemus, L. A., Hill, M. A. & Meininger, G. A. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure. Physiology (Bethesda) 24, 45–57 (2009).

    Google Scholar 

  13. Pries, A. R., Reglin, B. & Secomb, T. W. Remodeling of blood vessels: responses of diameter and wall thickness to hemodynamic and metabolic stimuli. Hypertension 46, 726–731 (2005).

    Article  Google Scholar 

  14. Zakrzewicz, A., Secomb, T. W. & Pries, A. R. Angioadaptation: keeping the vascular system in shape. News Physiol. Sci. 17, 197–201 (2002).

    PubMed  Google Scholar 

  15. Dzau, V. J. & Gibbons, G. H. Vascular remodeling: mechanisms and implications. J. Cardiovasc. Pharmacol. 21, S1–S5 (1993).

    Article  CAS  Google Scholar 

  16. Pries, A. R., Reglin, B. & Secomb, T. W. Structural adaptation of microvascular networks: functional roles of adaptive responses. Am. J. Physiol. 281, H1015–H1025 (2001).

    CAS  Google Scholar 

  17. Kamiya, A., Ando, J., Shibata, M. & Masuda, H. Roles of fluid shear stress in physiological regulation of vascular structure and function. Biorheology 25, 271–278 (1988).

    Article  CAS  Google Scholar 

  18. Langille, B. L. & O'Donnell, F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 231, 405–407 (1986).

    Article  CAS  Google Scholar 

  19. Langille, B. L. Arterial remodeling: relation to hemodynamics. Can. J. Physiol. Pharmacol. 74, 834–841 (1996).

    Article  CAS  Google Scholar 

  20. Rodbard, S. Vascular caliber. Cardiology 60, 4–49 (1975).

    Article  CAS  Google Scholar 

  21. Pries, A. R., Secomb, T. W. & Gaehtgens, P. Structural adaptation and stability of microvascular networks: theory and simulations. Am. J. Physiol. 275, H349–H360 (1998).

    CAS  PubMed  Google Scholar 

  22. Ellis, C. G., Bateman, R. M., Sharpe, M. D., Sibbald, W. J. & Gill, R. Effect of a maldistribution of microvascular blood flow on capillary O2 extraction in sepsis. Am. J. Physiol. Heart Circ. Physiol. 282, H156–H164 (2002).

    Article  CAS  Google Scholar 

  23. Pries, A. R., Reglin, B. & Secomb, T. W. Structural response of microcirculatory networks to changes in demand: information transfer by shear stress. Am. J. Physiol. 284, H2204–H2212 (2003).

    CAS  Google Scholar 

  24. Berne, R. M., Knabb, R. M., Ely, S. W. & Rubio, R. Adenosine in the local regulation of blood flow: a brief overview. Fed. Proc. 42, 3136–3142 (1983).

    CAS  PubMed  Google Scholar 

  25. Arciero, J. C., Carlson, B. E. & Secomb, T. W. Theoretical model of metabolic blood flow regulation: roles of ATP release by red blood cells and conducted responses. Am. J. Physiol. Heart Circ. Physiol. 295, H1562–H1571 (2008).

    Article  CAS  Google Scholar 

  26. Ellsworth, M. L. Red blood cell-derived ATP as a regulator of skeletal muscle perfusion. Med. Sci. Sports Exerc. 36, 35–41 (2004).

    Article  CAS  Google Scholar 

  27. Cosby, K. et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nature Med. 9, 1498–1505 (2003).

    Article  CAS  Google Scholar 

  28. Stamler, J. S. et al. Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 276, 2034–2037 (1997).

    Article  CAS  Google Scholar 

  29. Bakker, E. N. et al. Small artery remodeling depends on tissue-type transglutaminase. Circ. Res. 96, 119–126 (2005).

    Article  CAS  Google Scholar 

  30. Bakker, E. N. et al. Inward remodeling follows chronic vasoconstriction in isolated resistance arteries. J. Vasc. Res. 39, 12–20 (2002).

    Article  CAS  Google Scholar 

  31. Segal, S. S. & Duling, B. R. Flow control among microvessels coordinated by intercellular conduction. Science 234, 868–870 (1986).

    Article  CAS  Google Scholar 

  32. Figueroa, X. F. & Duling, B. R. Gap junctions in the control of vascular function. Antioxid. Redox Signal. 11, 251–266 (2009).

    Article  CAS  Google Scholar 

  33. de Wit, C., Wolfle, S. E. & Hopfl, B. Connexin-dependent communication within the vascular wall: contribution to the control of arteriolar diameter. Adv. Cardiol. 42, 268–283 (2006).

    Article  CAS  Google Scholar 

  34. Brisset, A. C., Isakson, B. E. & Kwak, B. R. Connexins in vascular physiology and pathology. Antioxid. Redox Signal. 11, 267–282 (2009).

    Article  CAS  Google Scholar 

  35. Little, T. L., Beyer, E. C. & Duling, B. R. Connexin 43 and connexin 40 gap junctional proteins are present in arteriolar smooth muscle and endothelium in vivo. Am. J. Physiol. 268, H729–H739 (1995).

    CAS  PubMed  Google Scholar 

  36. Johnstone, S., Isakson, B. & Locke, D. Biological and biophysical properties of vascular connexin channels. Int. Rev. Cell Mol. Biol. 278, 69–118 (2009).

    Article  Google Scholar 

  37. Wolfle, S. E. et al. Connexin45 cannot replace the function of connexin40 in conducting endothelium-dependent dilations along arterioles. Circ. Res. 101, 1292–1299 (2007).

    Article  Google Scholar 

  38. de Wit, C., Roos, F., Bolz, S. S. & Pohl, U. Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion. Physiol. Genomics 13, 169–177 (2003).

    Article  CAS  Google Scholar 

  39. Figueroa, X. F. et al. Central role of connexin40 in the propagation of electrically activated vasodilation in mouse cremasteric arterioles in vivo. Circ. Res. 92, 793–800 (2003).

    Article  CAS  Google Scholar 

  40. Liao, Y., Day, K. H., Damon, D. N. & Duling, B. R. Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice. Proc. Natl Acad. Sci. USA 98, 9989–9994 (2001).

    Article  CAS  Google Scholar 

  41. de Wit, C. Different pathways with distinct properties conduct dilations in the microcirculation in vivo. Cardiovasc. Res. 85, 604–613 (2010).

    Article  CAS  Google Scholar 

  42. Heyman, N. S., Kurjiaka, D. T., Ek Vitorin, J. F. & Burt, J. M. Regulation of gap junctional charge selectivity in cells coexpressing connexin 40 and connexin 43. Am. J. Physiol. Heart Circ. Physiol. 297, H450–H459 (2009).

    Article  CAS  Google Scholar 

  43. Bukauskas, F. F., Angele, A. B., Verselis, V. K. & Bennett, M. V. Coupling asymmetry of heterotypic connexin 45/ connexin 43-EGFP gap junctions: properties of fast and slow gating mechanisms. Proc. Natl Acad. Sci. USA 99, 7113–7118 (2002).

    Article  CAS  Google Scholar 

  44. Cottrell, G. T. & Burt, J. M. Heterotypic gap junction channel formation between heteromeric and homomeric Cx40 and Cx43 connexons. Am. J. Physiol. Cell Physiol. 281, C1559–C1567 (2001).

    Article  CAS  Google Scholar 

  45. Cottrell, G. T., Wu, Y. & Burt, J. M. Cx40 and Cx43 expression ratio influences heteromeric/ heterotypic gap junction channel properties. Am. J. Physiol. Cell Physiol. 282, C1469–C1482 (2002).

    Article  CAS  Google Scholar 

  46. Cottrell, G. T. & Burt, J. M. Functional consequences of heterogeneous gap junction channel formation and its influence in health and disease. Biochim. Biophys. Acta 1711, 126–141 (2005).

    Article  CAS  Google Scholar 

  47. Rackauskas, M. et al. Gating properties of heterotypic gap junction channels formed of connexins 40, 43, and 45. Biophys. J. 92, 1952–1965 (2007).

    Article  CAS  Google Scholar 

  48. Ebong, E. E., Kim, S. & DePaola, N. Flow regulates intercellular communication in HAEC by assembling functional Cx40 and Cx37 gap junctional channels. Am. J. Physiol. Heart Circ. Physiol. 290, H2015–H2023 (2006).

    Article  CAS  Google Scholar 

  49. Theis, M. et al. Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene. Genesis 29, 1–13 (2001).

    Article  CAS  Google Scholar 

  50. Gabriels, J. E. & Paul, D. L. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ. Res. 83, 636–643 (1998).

    Article  CAS  Google Scholar 

  51. Pries, A. R. et al. Structural adaptation and heterogeneity of normal and tumor microvascular networks. PLoS Comput. Biol. 5, e1000394 (2009).

    Article  Google Scholar 

  52. Ince, C. The microcirculation is the motor of sepsis. Crit. Care 9 (Suppl. 4) S13–S19 (2005).

    Article  Google Scholar 

  53. Tyml, K., Li, F. & Wilson, J. X. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit. Care Med. 33, 1823–1828 (2005).

    Article  CAS  Google Scholar 

  54. Lauterbach, M. et al. Shunting of the microcirculation after mesenteric ischemia and reperfusion is a function of ischemia time and increases mortality. Microcirculation 13, 411–422 (2006).

    Article  Google Scholar 

  55. Kruger, O. et al. Defective vascular development in connexin 45-deficient mice. Development 127, 4179–4193 (2000).

    CAS  PubMed  Google Scholar 

  56. Simon, A. M. & McWhorter, A. R. Vascular abnormalities in mice lacking the endothelial gap junction proteins connexin37 and connexin40. Dev. Biol. 251, 206–220 (2002).

    Article  CAS  Google Scholar 

  57. Simon, A. M. & McWhorter, A. R. Role of connexin37 and connexin40 in vascular development. Cell Commun. Adhes. 10, 379–385 (2003).

    Article  CAS  Google Scholar 

  58. Limaye, N., Boon, L. M. & Vikkula, M. From germline towards somatic mutations in the pathophysiology of vascular anomalies. Hum. Mol. Genet. 18, R65–R74 (2009).

    Article  CAS  Google Scholar 

  59. Brouillard, P. & Vikkula, M. Genetic causes of vascular malformations. Hum. Mol. Genet. 16, R140–R149 (2007).

    Article  CAS  Google Scholar 

  60. Tille, J. C. & Pepper, M. S. Hereditary vascular anomalies: new insights into their pathogenesis. Arterioscler. Thromb. Vasc. Biol. 24, 1578–1590 (2004).

    Article  CAS  Google Scholar 

  61. Buschmann, I. et al. Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis. Development 137, 2187–2196 (2010).

    Article  CAS  Google Scholar 

  62. Elzarrad, M. K. et al. Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium. BMC Med. 6, 20 (2008).

    Article  Google Scholar 

  63. van Beijnum, J. R. et al. Gene expression of tumor angiogenesis dissected: specific targeting of colon cancer angiogenic vasculature. Blood 108, 2339–2348 (2006).

    Article  CAS  Google Scholar 

  64. Seaman, S. et al. Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11, 539–554 (2007).

    Article  CAS  Google Scholar 

  65. Nebert, D. W. & Mason, H. S. An electron spin resonance study of neoplasms. Cancer Res. 23, 833–840 (1963).

    CAS  PubMed  Google Scholar 

  66. Chen, C. N., Hsieh, F. J., Cheng, Y. M., Chang, K. J. & Lee, P. H. Expression of inducible nitric oxide synthase and cyclooxygenase-2 in angiogenesis and clinical outcome of human gastric cancer. J. Surg. Oncol. 94, 226–233 (2006).

    Article  CAS  Google Scholar 

  67. Solan, J. L. et al. Phosphorylation at S365 is a gatekeeper event that changes the structure of Cx43 and prevents down-regulation by PKC. J. Cell Biol. 179, 1301–1309 (2007).

    Article  CAS  Google Scholar 

  68. Upham, B. L., Kang, K. S., Cho, H. Y. & Trosko, J. E. Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells. Carcinogenesis 18, 37–42 (1997).

    Article  CAS  Google Scholar 

  69. Suarez, S. & Ballmer-Hofer, K. VEGF transiently disrupts gap junctional communication in endothelial cells. J. Cell Sci. 114, 1229–1235 (2001).

    CAS  PubMed  Google Scholar 

  70. Fukumura, D. & Jain, R. K. Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc. Res. 74, 72–84 (2007).

    Article  CAS  Google Scholar 

  71. Jain, R. K., Finn, A. V., Kolodgie, F. D., Gold, H. K. & Virmani, R. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nature Clin. Pract. Cardiovasc. Med. 4, 491–502 (2007).

    Article  CAS  Google Scholar 

  72. Zhong, H. & Bowen, J. P. Antiangiogenesis drug design: multiple pathways targeting tumor vasculature. Curr. Med. Chem. 13, 849–862 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) grants CA040355 and HL034555. The authors thank B. Reglin for stimulating discussions and for help with figures 4–6.

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Authors and Affiliations

  1. Axel R. Pries and Michael Höpfner are at the Department of Physiology and the Centre for Cardiovascular Research, Charité Berlin, Thielallee 71, D-14195 Berlin, Germany.,

    Axel R. Pries & Michael Höpfner

  2. Axel R. Pries is also at the Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.,

    Axel R. Pries

  3. Ferdinand le Noble is at the Max-Delbrück-Centrum für Molekulare Medizin, D-13125 Berlin-Buch, Germany.,

    Ferdinand le Noble

  4. Mark W. Dewhirst is at the Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.,

    Mark W. Dewhirst

  5. Timothy W. Secomb is at the Department of Physiology, University of Arizona, Tucson, Arizona 85724, USA.,

    Timothy W. Secomb

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Glossary

Conducted response

A signal that is propagated along the wall of a blood vessel through the gap junctions that connect adjacent endothelial and/or smooth muscle cells. In a conducted vasomotor response, a stimulus applied at one point on a vessel elicits a contraction or dilation at another point. Some studies show that conducted responses can propagate for several millimetres without appreciable decay, implying that they regenerate themselves in a manner analogous to that used by nerve impulses.

Distal

Further from the heart. Capillaries are the most distal vessels.

Gap junction

A molecular structure that forms a passage connecting the cytoplasm of two adjacent cells and selectively allows solutes to pass between the cells. A gap junction consists of two linked hemichannels, called connexons, each embedded in the membrane of one of the cells. Each hemichannel consists of six connexins, which are proteins with multiple membrane-spanning domains.

Proximal

Closer to the heart — that is, upstream in arterial vessels and downstream in venous vessels.

Structural adaptation

Also known as vascular remodelling. Long-term changes in the structure of blood vessels (such as their diameter and wall mass) that occur during growth, in response to changing functional needs and in various disease states.

Wall shear stress

The mechanical tangential force per unit area that is exerted on the walls of blood vessels by flowing blood as a consequence of the blood viscosity. It is directed parallel to the surface of the wall in the direction of flow and is transmitted to the endothelial cells, which can respond to changes in wall shear stress. In a cylindrical microvessel, wall shear stress is given by the formula τ = (D/4) × (ΔP/L), where ΔP is the change in pressure, L is the length of the vessel, and D is the diameter of the vessel.

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Pries, A., Höpfner, M., le Noble, F. et al. The shunt problem: control of functional shunting in normal and tumour vasculature. Nat Rev Cancer 10, 587–593 (2010). https://doi.org/10.1038/nrc2895

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