Dynamic Control of Microvessel Diameters by Metabolic Factors

  • Axel R. PriesEmail author
  • Bettina Reglin


To maintain tissue function under steady state conditions and under increased workload, an adequate regulation of microvascular diameters is required. Microvessels continuously adapt to hemodynamic and metabolic stimuli. Vascular diameter increase in response to flow-induced shear stress establishes a positive feedback loop causing diameters of low-flow vessels to further decrease. This is balanced by metabolic signals released from vessels, tissue or red blood cells which can increase vascular diameters in undersupplied regions thus providing negative feedback regulation. Perturbation of these mechanisms leads to vascular maladaptation and microvascular dysfunction which underlies a multitude of clinical conditions possibly including myocardial angina in the absence of epicardial stenosis.


Vascular adaptation Maladaptation Conduction Shear stress Microvascular dysfunction Metabolic signals Feedback 


  1. 1.
    Pries AR, Secomb TW, Gaehtgens P. Structural adaptation and stability of microvascular networks: theory and simulations. Am J Phys. 1998;275:H349–60.Google Scholar
  2. 2.
    Pries AR, Reglin B, Secomb TW. Remodeling of blood vessels: responses of diameter and wall thickness to hemodynamic and metabolic stimuli. Hypertension. 2005;46:726–31.CrossRefGoogle Scholar
  3. 3.
    Reglin B, Pries AR. Metabolic control of microvascular networks: oxygen sensing and beyond. J Vasc Res. 2014;51:376–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Reglin B, Secomb TW, Pries AR. Structural adaptation of microvessel diameters in response to metabolic stimuli: where are the oxygen sensors? Am J Physiol Heart Circ Physiol. 2009;297:H2206–19.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Pries AR, Reglin B, Secomb TW. Structural adaptation of microvascular networks: functional roles of adaptive responses. Am J Phys. 2001;281:H1015–25.Google Scholar
  6. 6.
    Rodbard S. Vascular caliber. Cardiology. 1975;60:4–49.PubMedCrossRefGoogle Scholar
  7. 7.
    Reglin B, Secomb TW, Pries AR. Structural control of microvessel diameters: origins of metabolic signals. Front Physiol. 2017;8:813.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Pries AR, Badimon L, Bugiardini R, Camici PG, Dorobantu M, Duncker DJ, Escaned J, Koller A, Piek JJ, de Wit C. Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation. Eur Heart J. 2015;36:3134–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Pries AR, Hopfner M, Le Noble F, Dewhirst MW, Secomb TW. The shunt problem: control of functional shunting in normal and tumour vasculature. Nat Rev Cancer. 2010;10:587–93.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Phys. 1963;204:317–22.CrossRefGoogle Scholar
  11. 11.
    Golub AS, Pittman RN. Recovery of radial PO(2) profiles from phosphorescence quenching measurements in microvessels. Comp Biochem Physiol A Mol Integr Physiol. 2002;132:169–76.PubMedCrossRefGoogle Scholar
  12. 12.
    Ellsworth ML, Ellis CG, Goldman D, Stephenson AH, Dietrich HH, Sprague RS. Erythrocytes: oxygen sensors and modulators of vascular tone. Physiology (Bethesda). 2009;24:107–16.Google Scholar
  13. 13.
    Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO III, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med. 2003;9:1498–505.PubMedCrossRefGoogle Scholar
  14. 14.
    Stamler JS, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev. 2001;81:209–37.PubMedCrossRefGoogle Scholar
  15. 15.
    Secomb TW, Alberding JP, Hsu R, Dewhirst MW, Pries AR. Angiogenesis: an adaptive dynamic biological patterning problem. PLoS Comput Biol. 2013;9:e1002983.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Sprague RS, Hanson MS, Achilleus D, Bowles EA, Stephenson AH, Sridharan M, Adderley S, Procknow J, Ellsworth ML. Rabbit erythrocytes release ATP and dilate skeletal muscle arterioles in the presence of reduced oxygen tension. Pharmacol Rep. 2009;61:183–90.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Arciero JC, Carlson BE, Secomb TW. Theoretical model of metabolic blood flow regulation: roles of ATP release by red blood cells and conducted responses. Am J Physiol Heart Circ Physiol. 2008;295(4):H1562–71.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Koller A, Sun D, Kaley G. Role of shear stress and endothelial prostaglandins in flow- and viscosity-induced dilation of arterioles in vitro. Circ Res. 1993;72:1276–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Pries AR, Kuebler WM, Habazettl H. Coronary microcirculation in ischemic heart disease. Curr Pharm Des. 2018;24:2893–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Pries AR, Reglin B. Coronary microcirculatory pathophysiology: can we afford it to remain a black box? Eur Heart J. 2017;38:478–88.PubMedGoogle Scholar
  21. 21.
    Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in humans. J Am Coll Cardiol. 2009;54:281–92.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J. 2014;35:1101–11.PubMedCrossRefGoogle Scholar
  23. 23.
    Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356:830–40.PubMedCrossRefGoogle Scholar
  24. 24.
    Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries: a changing philosophy. JAMA. 2005;293:477–84.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Likoff W, Segal BL, Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med. 1967;276:1063–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Bugiardini R. Coronary microcirculation and ischemic heart disease, today. Curr Pharm Des. 2018;24:2891–2.PubMedCrossRefGoogle Scholar
  27. 27.
    Cannon RO III, Camici PG, Epstein SE. Pathophysiological dilemma of syndrome X 11. Circulation. 1992;85:883–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Agrawal S, Mehta PK, Bairey Merz CN. Cardiac syndrome X: update 2014 1. Cardiol Clin. 2014;32:463–78.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kaski JC, Aldama G, Cosin-Sales J. Cardiac syndrome X. Diagnosis, pathogenesis and management. Am J Cardiovasc Drugs. 2004;4:179–94.PubMedCrossRefGoogle Scholar
  30. 30.
    Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study 13. J Am Coll Cardiol. 1995;25:807–14.PubMedCrossRefGoogle Scholar
  31. 31.
    Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, Dorbala S, Blankstein R, Rimoldi O, Camici PG, Di Carli MF. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation. 2014;129:2518–27.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation. 2004;109:2518–23.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Bugiardini R. Women, ‘non-specific’ chest pain, and normal or near-normal coronary angiograms are not synonymous with favourable outcome. Eur Heart J. 2006;27:1387–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Kaski JC. Provocative tests for coronary artery spasm in MINOCA: necessary and safe? Eur Heart J. 2018;39:99–101.PubMedCrossRefGoogle Scholar
  35. 35.
    Pasupathy S, Tavella R, Beltrame JF. Myocardial infarction with nonobstructive coronary arteries (MINOCA): the past, present, and future management. Circulation. 2017;135:1490–3.PubMedCrossRefGoogle Scholar
  36. 36.
    Agewall S, Beltrame JF, Reynolds HR, Niessner A, Rosano G, Caforio AL, De CR, Zimarino M, Roffi M, Kjeldsen K, Atar D, Kaski JC, Sechtem U, Tornvall P. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J. 2017;38:143–53.PubMedGoogle Scholar
  37. 37.
    Bugiardini R, Badimon L, Collins P, Erbel R, Fox K, Hamm C, Pinto F, Rosengren A, Stefanadis C, Wallentin L, Van de Werf F. Angina, “normal” coronary angiography, and vascular dysfunction: risk assessment strategies. PLoS Med. 2007;4:e12.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Marinescu MA, Loffler AI, Ouellette M, Smith L, Kramer CM, Bourque JM. Coronary microvascular dysfunction, microvascular angina, and treatment strategies 1. JACC Cardiovasc Imaging. 2015;8:210–20.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Verdant CL, De BD, Bruhn A, Clausi CM, Su F, Wang Z, Rodriguez H, Pries AR, Vincent JL. Evaluation of sublingual and gut mucosal microcirculation in sepsis: a quantitative analysis. Crit Care Med. 2009;37:2875–81.PubMedCrossRefGoogle Scholar
  40. 40.
    Lipinska-Gediga M. Sepsis and septic shock-is a microcirculation a main player? Anaesthesiol Intensive Ther. 2016;48:261–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Potter EK, Hodgson L, Creagh-Brown B, Forni LG. Manipulating the microcirculation in sepsis - the impact of vasoactive medications on microcirculatory blood flow. A systematic review. Shock. 2019;52(1):5–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Pries AR, Cornelissen AJ, Sloot AA, Hinkeldey M, Dreher MR, Hopfner M, Dewhirst MW, Secomb TW. Structural adaptation and heterogeneity of normal and tumor microvascular networks. PLoS Comput Biol. 2009;5:e1000394.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Secomb TW, Dewhirst MW, Pries AR. Structural adaptation of normal and tumour vascular networks. Basic Clin Pharmacol Toxicol. 2012;110:63–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of PhysiologyCharité Universitätsmedizin BerlinBerlinGermany
  2. 2.Deutsches Herzzentrum BerlinBerlinGermany

Personalised recommendations