Angioplasticity and Cerebrovascular Remodeling

  • Joseph C. LaManna
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (volume 737)


Up until recently, the prevailing view was that the structure of the mammalian brain was set during development and remained unchanged thereafter. Fifty years ago there were discussions and arguments on the existence of synaptic plasticity in brain and spinal cord that eventually established that at least the neurons could undergo continued structural rearrangements. Now it appears that there is much more plasticity in the CNS than previously conceived, extending to the vascular tree down to the level of the capillaries. With the introduction of the concept of the neurovascular unit it became clear that neurons, glia, and endothelial cells are capable of active reorganization throughout adult life. This plasticity has significant implications for brain function and pathophysiology. Apparently, capillary density is coupled to oxygen sufficiency. Consistently increased neuronal activity, for example during motor training exercises, leads to increased capillary density. Chronic hypoxic exposure, such as occurs, for example, during sojourns at altitude also lead to increased capillary density. Important components of the capillary plasticity regulation mechanism are the HIF-1 and HIF-2 transcription factors that regulate vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) acting through prostaglandin E and angiopoietin-2 (ang-2). With age, the HIF-1 signaling pathway becomes attenuated due to increased prolyl hydoxylase activity probably as a result of increased reactive oxygen species, which changes the set point for tissue oxygen detection. Thus, plasticity becomes increasingly impaired with aging making learning more difficult and increasing the brain vulnerability to cerebrovascular challenges. The increased cerebrovascular vulnerability with age suggests a potential strategy for treating cerebrovascular diseases like stroke and dementia. The strategy involves agents that restore or augment HIF-1 function. Augmentation of HIF-1 may be the prime mechanism for preconditioning and neuroprotection. One such strategy is through a ketogenic diet that leads to HIF-1 accumulation due to inhibition of prolyl hydroxylase. Discovery of angioplasticity has opened up new areas for research that elucidates brain function, provides new explanations for the neuropathology following cerebrovascular injury and dementia, and suggests potential new therapeutic approaches to prevent or resolve these insults.


Vascular Endothelial Growth Factor Blood Oxygen Level Dependent Ketogenic Diet Capillary Density Hypobaric Hypoxia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from the USA National Institutes of Health NS38632, HL092933 and NS062048.


  1. 1.
    Simpson IA, Carruthers A, Vannucci SJ (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27:1766–1791PubMedCrossRefGoogle Scholar
  2. 2.
    Ndubuizu O, LaManna JC (2007) Brain tissue oxygen concentration measurements. Antioxid Redox Signal 9:1207–1219PubMedCrossRefGoogle Scholar
  3. 3.
    Sanganahalli BG, Herman P, Blumenfeld H, Hyder F (2009) Oxidative neuroenergetics in event-related paradigms. J Neurosci 29:1707–1718PubMedCrossRefGoogle Scholar
  4. 4.
    Sokoloff L (1981) Relationships among local functional activity, energy metabolism, and blood flow in the central nervous system. Fed Proc 40:2311–2316PubMedGoogle Scholar
  5. 5.
    Baron JC, Rougemont D, Soussaline F, Bustany P, Crouzel C, Bousser MG, Comar D (1984) Local interrelationships of cerebral oxygen consumption and glucose utilization in normal subjects and in ischemic stroke patients: a positron tomography study. J Cereb Blood Flow Metab 4:140–149PubMedCrossRefGoogle Scholar
  6. 6.
    Leenders KL, Perani D, Lammertsma AA, Heather JD, Buckingham P, Healy MJ, Gibbs JM, Wise RJ, Hatazawa J, Herold S (1990) Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain 113(Pt 1):27–47PubMedCrossRefGoogle Scholar
  7. 7.
    LaManna JC, McCracken KA, Strohl KP (1989) Changes in regional cerebral blood flow and sucrose space after 3-4 weeks of hypobaric hypoxia (0.5 ATM). Adv Exp Med Biol 248:471–477PubMedCrossRefGoogle Scholar
  8. 8.
    LaManna JC, Vendel LM, Farrell RM (1992) Brain adaptation to chronic hypobaric hypoxia in rats. J Appl Physiol 72:2238–2243PubMedGoogle Scholar
  9. 9.
    Lauro KL, LaManna JC (1997) Adequacy of cerebral vascular remodeling following three weeks of hypobaric hypoxia. Examined by an integrated composite analytical model. Adv Exp Med Biol 411:369–376PubMedCrossRefGoogle Scholar
  10. 10.
    Chávez JC, Agani F, Pichiule P, LaManna JC (2000) Expression of hypoxic inducible factor 1α in the brain of rats during chronic hypoxia. J Appl Physiol 89:1937–1942PubMedGoogle Scholar
  11. 11.
    Chavez JC, Baranova O, Lin J, Pichiule P (2006) The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci 26:9471–9481PubMedCrossRefGoogle Scholar
  12. 12.
    LaManna JC, Chavez JC, Pichiule P (2007) Genetics and gene expression of glycolysis. In: Gibson GE, Dienel GA (eds) Brain energetics, integration of molecular and cellular processes, 3rd edn. Springer, Berlin, pp 771–788Google Scholar
  13. 13.
    LaManna JC (2007) Hypoxia in the central nervous system. Essays Biochem 43:139–152PubMedCrossRefGoogle Scholar
  14. 14.
    Xu K, LaManna JC (2006) Chronic hypoxia and the cerebral circulation. J Appl Physiol 100:725–730PubMedCrossRefGoogle Scholar
  15. 15.
    LaManna JC, Chavez JC, Pichiule P (2004) Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol 207:3163–3169PubMedCrossRefGoogle Scholar
  16. 16.
    Ndubuizu OI, Chavez JC, LaManna JC (2009) Increased prolyl 4-hydroxylase expression and differential regulation of hypoxia-inducible factors in the aged rat brain. Am J Physiol Regul Integr Comp Physiol 297:R158–R165PubMedCrossRefGoogle Scholar
  17. 17.
    Pichiule P, LaManna JC (2002) Angiopoietin-2 and rat brain capillary remodeling during adaptation and de-adaptation to prolonged mild hypoxia. J Appl Physiol 93:1131–1139PubMedGoogle Scholar
  18. 18.
    Pichiule P, Chavez JC, LaManna JC (2004) Hypoxic regulation of angiopoietin-2 expression in endothelial cells. J Biol Chem 279:12171–12180PubMedCrossRefGoogle Scholar
  19. 19.
    Dore-Duffy P, LaManna JC (2007) Physiologic angiodynamics in the brain. Antioxid Redox Signal 9:1363–1371PubMedCrossRefGoogle Scholar
  20. 20.
    Puchowicz MA, Xu K, Sun X, Ivy A, Emancipator D, LaManna JC (2007) Diet-induced ketosis increases capillary density without altered blood flow in rat brain. Am J Physiol Endocrinol Metab 292:E1607–E1615PubMedCrossRefGoogle Scholar
  21. 21.
    Puchowicz MA, Zechel JL, Valerio J, Emancipator DS, Xu K, Pundik S, LaManna JC, Lust WD (2008) Neuroprotection in diet-induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab 28:1907–1916PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Physiology and BiophysicsCase Western Reserve UniversityClevelandUSA
  2. 2.Department of Neurology (BRB 525)Case Western Reserve University School of MedicineClevelandUSA

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