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Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization


Cerebral microvascular occlusion is a common phenomenon throughout life1,2 that might require greater recognition as a mechanism of brain pathology. Failure to recanalize microvessels promptly may lead to the disruption of brain circuits and significant functional deficits3. Haemodynamic forces and the fibrinolytic system4 are considered to be the principal mechanisms responsible for recanalization of occluded cerebral capillaries and terminal arterioles. Here we identify a previously unrecognized cellular mechanism that may also be critical for this recanalization. By using high-resolution fixed-tissue microscopy and two-photon imaging in living mice we observed that a large fraction of microemboli infused through the internal carotid artery failed to be lysed or washed out within 48 h. Instead, emboli were found to translocate outside the vessel lumen within 2–7 days, leading to complete re-establishment of blood flow and sparing of the vessel. Recanalization occurred by a previously unknown mechanism of microvascular plasticity involving the rapid envelopment of emboli by endothelial membrane projections that subsequently form a new vessel wall. This was followed by the formation of an endothelial opening through which emboli translocated into the perivascular parenchyma. The rate of embolus extravasation was significantly decreased by pharmacological inhibition of matrix metalloproteinase 2/9 activity. In aged mice, extravasation was markedly delayed, resulting in persistent tissue hypoxia, synaptic damage and cell death. Alterations in the efficiency of the protective mechanism that we have identified may have important implications in microvascular pathology, stroke recovery and age-related cognitive decline.

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Figure 1: Emboli that fail to be washed out undergo extravasation leading to re-establishment of blood flow.
Figure 2: Focal endothelial remodelling underlies the translocation of emboli.
Figure 3: MMP-2/9 activity is induced around the occlusion site.
Figure 4: Delayed extravasation in ageing contributes to persistent hypoxia, synaptic injury and cell death.


  1. Siebler, M., Kleinschmidt, A., Sitzer, M., Steinmetz, H. & Freund, H. J. Cerebral microembolism in symptomatic and asymptomatic high-grade internal carotid artery stenosis. Neurology 44, 615–618 (1994)

    CAS  Article  Google Scholar 

  2. Markus, H. S., Thomson, N. D. & Brown, M. M. Asymptomatic cerebral embolic signals in symptomatic and asymptomatic carotid artery disease. Brain 118, 1005–1011 (1995)

    Article  Google Scholar 

  3. Vermeer, S. E. et al. Silent brain infarcts and the risk of dementia and cognitive decline. N. Engl. J. Med. 348, 1215–1222 (2003)

    Article  Google Scholar 

  4. Collen, D. On the regulation and control of fibrinolysis. Edward Kowalski Memorial Lecture. Thromb. Haemost. 43, 77–89 (1980)

    CAS  Article  Google Scholar 

  5. Powers, W. J., Grubb, R. L. Jr, Darriet, D. & Raichle, M. E. Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J. Cereb. Blood Flow Metab. 5, 600–608 (1985)

    CAS  Article  Google Scholar 

  6. Levin, E. G. & del Zoppo, G. J. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am. J. Pathol. 144, 855–861 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Zlokovic, B. V. et al. Expression of tissue plasminogen activator in cerebral capillaries: possible fibrinolytic function of the blood–brain barrier. Neurosurgery 37, 955–961 (1995)

    CAS  Article  Google Scholar 

  8. Rapp, J. H. et al. Atheroemboli to the brain: size threshold for causing acute neuronal cell death. J. Vasc. Surg. 32, 68–76 (2000)

    CAS  Article  Google Scholar 

  9. Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002)

    ADS  CAS  Article  Google Scholar 

  10. Muller, W. A. Leukocyte–endothelial–cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 24, 327–334 (2003)

    CAS  PubMed  Google Scholar 

  11. Engelhardt, B. & Wolburg, H. Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house? Eur. J. Immunol. 34, 2955–2963 (2004)

    CAS  Article  Google Scholar 

  12. Dejana, E. Endothelial cell–cell junctions: happy together. Nature Rev. Mol. Cell Biol. 5, 261–270 (2004)

    CAS  Article  Google Scholar 

  13. Kamei, M. et al. Endothelial tubes assemble from intracellular vacuoles in vivo . Nature 442, 453–456 (2006)

    ADS  CAS  Article  Google Scholar 

  14. Carman, C. V. & Springer, T. A. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J. Cell Biol. 167, 377–388 (2004)

    CAS  Article  Google Scholar 

  15. Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006)

    ADS  CAS  Article  Google Scholar 

  16. Yang, Y., Estrada, E. Y., Thompson, J. F., Liu, W. & Rosenberg, G. A. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J. Cereb. Blood Flow Metab. 27, 697–709 (2007)

    CAS  Article  Google Scholar 

  17. Stratman, A. N. et al. Endothelial cell lumen and vascular guidance tunnel formation requires MT1-MMP-dependent proteolysis in 3-dimensional collagen matrices. Blood 114, 237–247 (2009)

    CAS  Article  Google Scholar 

  18. Page-McCaw, A., Ewald, A. J. & Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nature Rev. Mol. Cell Biol. 8, 221–233 (2007)

    CAS  Article  Google Scholar 

  19. Farkas, E. & Luiten, P. G. Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog. Neurobiol. 64, 575–611 (2001)

    CAS  Article  Google Scholar 

  20. Zhao, B. Q. et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nature Med. 12, 441–445 (2006)

    CAS  Article  Google Scholar 

  21. Zhang, S., Boyd, J., Delaney, K. & Murphy, T. H. Rapid reversible changes in dendritic spine structure in vivo gated by the degree of ischemia. J. Neurosci. 25, 5333–5338 (2005)

    CAS  Article  Google Scholar 

  22. Nishimura, N. et al. Targeted insult to subsurface cortical blood vessels using ultrashort laser pulses: three models of stroke. Nature Methods 3, 99–108 (2006)

    CAS  Article  Google Scholar 

  23. Gleerup, G. & Winther, K. The effect of ageing on platelet function and fibrinolytic activity. Angiology 46, 715–718 (1995)

    CAS  Article  Google Scholar 

  24. Arvanitakis, Z., Wilson, R. S., Bienias, J. L., Evans, D. A. & Bennett, D. A. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch. Neurol. 61, 661–666 (2004)

    Article  Google Scholar 

  25. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nature Rev. Neurosci. 5, 347–360 (2004)

    CAS  Article  Google Scholar 

  26. Lo, E. H., Dalkara, T. & Moskowitz, M. A. Mechanisms, challenges and opportunities in stroke. Nature Rev. Neurosci. 4, 399–415 (2003)

    CAS  Article  Google Scholar 

  27. Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte–endothelial interactions at the blood-brain barrier. Nature Rev. Neurosci. 7, 41–53 (2006)

    CAS  Article  Google Scholar 

  28. Zlokovic, B. V. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008)

    CAS  Article  Google Scholar 

  29. Pugsley, W. et al. The impact of microemboli during cardiopulmonary bypass on neuropsychological functioning. Stroke 25, 1393–1399 (1994)

    CAS  Article  Google Scholar 

  30. Kleinfeld, D., Mitra, P. P., Helmchen, F. & Denk, W. Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc. Natl Acad. Sci. USA 95, 15741–15746 (1998)

    ADS  CAS  Article  Google Scholar 

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We thank S. Lo, C. Freitas, D. Choi and C. Whiteus for help with experiments; A. Schain for suggesting the use of ACTB–eGFP mice; E. Mugnaini for advice with transmission electron microscopy experiments; and G. D’avossa, J. García-Añoveros, J. Kessler and P. Opal for helpful discussions and critical review of the manuscript. This work was supported by National Institutes of Health/National Institute on Aging grant AG027855 (J.G.) and a Howard Hughes Medical Institute medical student research fellowship (C.K.L.).

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Authors and Affiliations



J.G., C.K.L. and T.Y. conceived and designed the project. C.K.L., T.Y., B.H. and J.G. performed in vivo two-photon imaging. C.K.L., B.H. and J.G. adapted the technique and performed electron microscopy experiments. C.K.L. and T.Y. performed in situ zymography, ageing mice and SB-3CT experiments. T.Y. performed cell culture and the imaging experiment on human umbilical-vein endothelial cells. Z.L., C.K.L., T.Y., B.H. and J.G. performed histological and confocal microscopy experiments. J.G. wrote the manuscript with significant input from C.K.L. and T.Y.

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Correspondence to Jaime Grutzendler.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14 with legends and legends for Supplementary Movies 1-5. (PDF 1611 kb)

Supplementary Movie 1

This movie shows embolus in the process of extravasation – see Supplementary Information file for full legend. (MOV 22465 kb)

Supplementary Movie 2

This movie shows embolus extravasation and reestablishment of blood flow – see Supplementary Information file for full legend. (MOV 2156 kb)

Supplementary Movie 3

This movie shows microsphere extravasation – see Supplementary Information file for full legend. (MOV 6848 kb)

Supplementary Movie 4

This movie shows early extravasation and reestablishment of blood flow – see Supplementary Information file for full legend. (MOV 1378 kb)

Supplementary Movie 5

This movie shows cholesterol embolus occlusion – see Supplementary Information file for full legend. (MOV 778 kb)

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Lam, C., Yoo, T., Hiner, B. et al. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature 465, 478–482 (2010).

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