Hypoxia, Arterial Blood Pressure, and Microcirculation

  • Jean-Jacques Mourad
  • Jean-Sébastien Silvestre
  • Bernard I. LévyEmail author


The larger part of the systemic hemodynamic resistance is located in the microcirculation. The microcirculatory networks, especially its arteriolar and capillary components, are subjected to angiogenesis in relation to the activation of the HIF-VEGF-NO pathways. In the present chapter we report experiments performed in young and adult spontaneously hypertensive rats maintained for several weeks under chronic hypoxic conditions. Chronic hypoxia resulted in activation of VEGF-induced angiogenesis, increases in myocardial and skeletal muscle capillary density, and normalization of arterial blood pressure in both young prehypertensive rats and old rats with established hypertension.

In parallel and in contrast, administration of bevacizumab, an antibody directed against the VEGF protein, to patients with metastatic colorectal cancer, induced a significant increase in blood pressure in relation to a significant reduction in capillary density and a complete blunting of the endothelial function.

Taken together, these experimental and clinical results suggest that angiogenesis and antiangiogenesis could have rapid and marked effects on the peripheral resistance. Moreover, the density of the capillary bed seems to play a major role in the control of the arterial pressure.


Arterial hypertension Microcirculation Angiogenesis VEGF Bevacizumab 


  1. 1.
    Feihl F, Liaudet L, Waeber B, Levy BI. Hypertension: a disease of the microcirculation? Hypertension. 2006;48:1012–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation. 2001;104:735–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Levy BI, Duriez M, Samuel JL. Coronary microvasculature alteration in hypertensive rats. Effect of treatment with a diuretic and an ACE inhibitor. Am J Hypertens. 2001;14:7–13.PubMedCrossRefGoogle Scholar
  4. 4.
    Sabri A, Samuel JL, Marotte F, Poitevin P, Rappaport L, Levy BI. Microvasculature in angiotensin II-dependent cardiac hypertrophy in the rat. Hypertension. 1998;32:371–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Chen II, Prewitt RL, Dowell RF. Microvascular rarefaction in spontaneously hypertensive rat cremaster muscle. Am J Physiol. 1981;241:H306–10.PubMedGoogle Scholar
  6. 6.
    Antonios TF, Rattray FM, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Rarefaction of skin capillaries in normotensive offspring of individuals with essential hypertension. Heart. 2003;89:175–8.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Noon JP, Walker BR, Webb DJ, Shore AC, Holton DW, Edwards HV, Watt GC. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest. 1997;99:1873–9.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9:653–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Blanes MG, Oubaha M, Rautureau Y, Gratton JP. Phosphorylation of tyrosine 801 of the VEGFR-2 is necessary for AKT-dependent eNOS activation and nitric oxide release from endothelial cells. J Biol Chem. 2007;282:10660–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Janssens SP, Thompson BT, Spence CR, Hales CA. Functional and structural changes with hypoxia in pulmonary circulation of spontaneously hypertensive rats. J Appl Physiol. 1994;77:1101–7.PubMedGoogle Scholar
  11. 11.
    Henley WN, Tucker A. Hypoxic moderation of systemic hypertension in the spontaneously hypertensive rat. Am J Physiol. 1987;252:R554–61.PubMedGoogle Scholar
  12. 12.
    Mifflin S. New insights into the electrophysiology of brainstem circuits controlling blood pressure. Curr Hypertens Rep. 2007;9:236–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Hainsworth R, Drinkhill MJ, Rivera-Chira M. The autonomic nervous system at high altitude. Clin Auton Res. 2007;17:13–9.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Rice TB, Strollo Jr PJ, Morrell MJ. Update in sleep medicine 2011. Am J Respir Crit Care Med. 2012;185:1271–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Kapa S, Sert Kuniyoshi FH, Somers VK. Sleep apnea and hypertension: interactions and implications for management. Hypertension. 2008;51:605–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Sullivan JM, Prewitt RL, Josephs JA. Attenuation of the microcirculation in young patients with high-output borderline hypertension. Hypertension. 1983;5:844–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Gasser P, Buhler FR. Nailfold microcirculation in normotensive and essential hypertensive subjects, as assessed by video-microscopy. J Hypertens. 1992;10:83–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Debbabi H, Uzan L, Mourad JJ, Safar M, Levy BI, Tibirica E. Increased skin capillary density in treated essential hypertensive patients. Am J Hypertens. 2006;19:477–83.PubMedCrossRefGoogle Scholar
  19. 19.
    Gleadle JM, Ratcliffe PJ. Hypoxia and the regulation of gene expression. Mol Med Today. 1998;4:122–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Berra E, Ginouves A, Pouyssegur J. The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep. 2006;7:41–5.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Brogi E, Schatteman G, Wu T, Kim EA, Varticovski L, Keyt B, Isner JM. Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest. 1996;97:469–76.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci U S A. 1998;95:15809–14.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest. 1995;95:1798–807.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Waltenberger J, Mayr U, Pentz S, Hombach V. Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation. 1996;94:1647–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Wang H, Olszewski B, Rosebury W, Wang D, Robertson A, Keiser JA. Impaired angiogenesis in SHR is associated with decreased KDR and MT1-MMP expression. Biochem Biophys Res Commun. 2004;315:363–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Silvestre JS, Bergaya S, Tamarat R, Duriez M, Boulanger CM, Levy BI. Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway. Circ Res. 2001;89:678–83.PubMedCrossRefGoogle Scholar
  27. 27.
    Silvestre JS, Kamsu-Kom N, Clergue M, Duriez M, Levy BI. Very low dose combination of the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide induces an early and sustained increase in neovascularization in rat ischemic legs. J Pharmacol Exp Ther. 2002;303:1038–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Sica DA. Angiogenesis inhibitors and hypertension: an emerging issue. J Clin Oncol. 2006;24:1329–31.PubMedCrossRefGoogle Scholar
  29. 29.
    Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006;354:980–2.PubMedCrossRefGoogle Scholar
  30. 30.
    Allen JA, Adlakha A, Bergethon PR. Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer. Arch Neurol. 2006;63:1475–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Hood JD, Meininger CJ, Ziche M, et al. VEGF upregulates eNOS message, protein, and NO production in human endothelial cells. Am J Physiol. 1998;274:H1054–8.PubMedGoogle Scholar
  32. 32.
    Shen BQ, Lee DY, Zioncheck TF. Vascular endothelial growth factor governs nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem. 1999;274:33057–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Zou AP, Cowley AW. Role of nitric oxide in the control of renal function and salt sensitivity. Curr Hypertens Rep. 1999;1:178–86.PubMedCrossRefGoogle Scholar
  34. 34.
    Horowitz JR, Rivard A, van der Zee R, et al. Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. Arterioscler Thromb Vasc Biol. 1997;17:2793–800.PubMedCrossRefGoogle Scholar
  35. 35.
    Kamba T, Tam BY, Hashizume H, et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290:H560–76.PubMedCrossRefGoogle Scholar
  36. 36.
    Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35–52.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Baffert F, Le T, Sennino B, et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. Am J Physiol Heart Circ Physiol. 2006;290:H547–59.PubMedCrossRefGoogle Scholar
  38. 38.
    Kamba T, McDonald DM. Mechanisms of adverse effects of anti- VEGF therapy for cancer. Br J Cancer. 2007;96:1788–95.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008;19:927–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Steeghs N, Gelderblom H, Roodt JO, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14:3470–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Ruedemann AD. Conjunctival vessels. JAMA. 1933;101:1477–81.CrossRefGoogle Scholar
  42. 42.
    Serne EH, Gans ROB, ter Maaten JC, et al. Impaired skin capillary recruitment in essential hypertension is caused by both functional and structural capillary rarefaction. Hypertension. 2001;38:238–42.PubMedCrossRefGoogle Scholar
  43. 43.
    Antonios TFT, Singer DRJ, Markandu ND, et al. Structural skin capillary rarefaction in essential hypertension. Hypertension. 1999;33:998–1001.PubMedCrossRefGoogle Scholar
  44. 44.
    Prasad A, Dunnill GS, Mortimer PS, MacGregor GA. Capillary rarefaction in the forearm skin in essential hypertension. J Hypertens. 1995;13:265–8.PubMedGoogle Scholar
  45. 45.
    Lee PC, Salyapongse AN, Bragdon GA, et al. Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol. 1999;277:H1600–8.PubMedGoogle Scholar
  46. 46.
    Kiefer FN, Misteli H, Kalak N, et al. Inhibition of NO biosynthesis, but not elevated blood pressure, reduces angiogenesis in rat models of secondary hypertension. Blood Press. 2002;11:116–24.PubMedCrossRefGoogle Scholar
  47. 47.
    Prewitt RL, Hashimoto H, Stacy DL. Structural and functional rarefaction of microvessels in hypertension. In: Lee R, editor. Blood vessel changes in hypertension: structure and function. Boca Raton: CRC Press; 1990. p. 71–90.Google Scholar
  48. 48.
    Steeghs N, Rabelink TJ, op ‘t Roodt J, et al. Reversibility of capillary density after discontinuation of bevacizumab treatment. Ann Oncol. 2010;21:1100–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Franklin PH, Banfor PN, Tapang P, et al. Effect of the multitargeted receptor tyrosine kinase inhibitor, ABT-869, on blood pressure in conscious rats and mice: reversal with antihypertensive agents and effect on tumor growth inhibition. J Pharmacol Exp Ther. 2009;329:928–37.PubMedCrossRefGoogle Scholar
  50. 50.
    Bono P, Elfving H, Utriainen T, Osterlund P, Saarto T, Alanko T, et al. Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma. Ann Oncol. 2009;20:393–4.PubMedCrossRefGoogle Scholar
  51. 51.
    Levy BI. Blood pressure as a potential biomarker of the efficacy angiogenesis inhibitor. Ann Oncol. 2009;20:200–3.PubMedCrossRefGoogle Scholar
  52. 52.
    Serebrovskaya TV, Manukhina EB, Smith ML, Downey HF, Mallet RT. Intermittent hypoxia: cause of or therapy for systemic hypertension? Exp Biol Med. 2008;233:627–50.CrossRefGoogle Scholar
  53. 53.
    Faeh D, Gutzwiller F, Bopp M, Swiss National Cohort Study Group. Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation. 2009;120:495–501.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Jean-Jacques Mourad
    • 1
  • Jean-Sébastien Silvestre
    • 2
  • Bernard I. Lévy
    • 2
    • 3
    Email author
  1. 1.Department of Internal Medicine and Arterial HypertensionAvicenne University Hospital – APHPBobignyFrance
  2. 2.Cardiovascular Research Center- Inserm UMRS 970ParisFrance
  3. 3.Blood and Vessel InstituteParisFrance

Personalised recommendations