Penetrating arterioles are a bottleneck in the perfusion of neocortex
Open accessAbstract
Penetrating arterioles bridge the mesh of communicating arterioles on the surface of cortex with the subsurface microvascular bed that feeds the underlying neural tissue. We tested the conjecture that penetrating arterioles, which are positioned to regulate the delivery of blood, are loci of severe ischemia in the event of occlusion. Focal photothrombosis was used to occlude single penetrating arterioles in rat parietal cortex, and the resultant changes in flow of red blood cells were measured with two-photon laser-scanning microscopy in individual subsurface microvessels that surround the occlusion. We observed that the average flow of red blood cells nearly stalls adjacent to the occlusion and remains within 30% of its baseline value in vessels as far as 10 branch points downstream from the occlusion. Preservation of average flow emerges 350 μm away; this length scale is consistent with the spatial distribution of penetrating arterioles. We conclude that penetrating arterioles are a bottleneck in the supply of blood to neocortex, at least to superficial layers.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Penetrating arterioles and venules form bottlenecks in the blood supply to neighborhoods of microvessels.
“Past work shows that penetrating arterioles11 and venules12 form bottlenecks in the supply of blood to neighborhoods of microvessels.”
From The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit (2013) · cites this paper as [11]
Cites
Paxinos, G. (1985) · Cited by 3,715 · see citing works
Neurovascular regulation in the normal brain and in Alzheimer's disease
Iadecola, C. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1387 · Cited by 2,213 · see citing works
O'Brien, J. T., Erkinjuntti, T., Reisberg, ., Román, G. C., Pantoni, L., Bowler, J., Ballard, C., DeCarli, C., Gorelick, P., Rockwood, K., et al. (2014) · International Journal of Stroke · doi:10.1111/ijs.12374_18 · Cited by 1,165 · see citing works
O'Brien, J. T., Erkinjuntti, T., Reisberg, B., Roman, G., Sawada, T., Pantoni, L., Bowler, J. V., Ballard, C., DeCarli, C., Gorelick, P. B., et al. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00305-3 · Cited by 1,139 · see citing works
Imaging of angiogenesis: from microscope to clinic
McDonald, D. M., & Choyke, P. L. (2003) · Nature Medicine · doi:10.1038/nm0603-713 · Cited by 1,020 · see citing works
Kleinfeld, D., Mitra, P. P., Helmchen, F., & Denk, W. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15741 · Cited by 832 · see citing works
Self-citationIn vivo dendritic calcium dynamics in neocortical pyramidal neurons
Svoboda, K., Denk, W. T., Kleinfeld, D., & Tank, D. W. (1997) · Nature · doi:10.1038/385161a0 · Cited by 820 · see citing works
Self-citationThe arterial lesions underlying lacunes
Fisher, C. M. (1969) · Acta Neuropathologica · doi:10.1007/bf00685305 · Cited by 755 · see citing works
Moody, D. M., Bell, M. A., & CHALLA, V. R. (1990) · PubMed · Cited by 416 · see citing works
Schaffer, C. B., Friedman, B., Nishimura, N., Schroeder, L. F., Tsai, P. S., Ebner, F. F., Lyden, P. D., & Kleinfeld, D. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040022 · Cited by 400 · see citing works
Self-citationNishimura, N., Schaffer, C. B., Friedman, B., Tsai, P. S., Lyden, P. D., & Kleinfeld, D. (2006) · Nature Methods · doi:10.1038/nmeth844 · Cited by 308 · see citing works
Self-citationTwo-photon imaging of capillary blood flow in olfactory bulb glomeruli
Chaigneau, E. M., Oheim, M., Audinat, É., & Charpak, S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2133652100 · Cited by 306 · see citing works
Neuropathologic Substrates of Ischemic Vascular Dementia
Vinters, H. V., Ellis, W. G., Zarow, C., Zaias, B. W., Jagust, W. J., Mack, W. J., & Chui, H. C. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.11.931 · Cited by 304 · see citing works
Woolsey, T. A., Rovainen, C. M., Cox, S. B., Henegar, M. H., Liang, G. E., Liu, D., Moskalenko, Y. E., Sui, J., & Wei, L. (1996) · Cerebral Cortex · doi:10.1093/cercor/6.5.647 · Cited by 276 · see citing works
Rapid Reversible Changes in Dendritic Spine Structure<i>In Vivo</i>Gated by the Degree of Ischemia
Zhang, S., Boyd, J., Delaney, K., & Murphy, T. H. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1085-05.2005 · Cited by 267 · see citing works
Anatomy and Functionality of Leptomeningeal Anastomoses: A Review
Brozici, M., van der Zwan, A., & Hillen, B. (2003) · Stroke · doi:10.1161/01.str.0000095791.85737.65 · Cited by 249 · see citing works
Blood Capillary Distribution Correlates with Hemodynamic-based Functional Imaging in Cerebral Cortex
Harrison, R. V. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.3.225 · Cited by 231 · see citing works
Cortical Microinfarcts and Demyelination Significantly Affect Cognition in Brain Aging
Kövari, E., Gold, G., Herrmann, F. R., Canuto, A., Hof, P. R., Michel, J.-P., Bouras, C., & Giannakopoulos, P. (2004) · Stroke · doi:10.1161/01.str.0000110791.51378.4e · Cited by 202 · see citing works
Cox, S. B., Woolsey, T. A., & Rovainen, C. M. (1993) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1993.113 · Cited by 198 · see citing works
Testing the validity of the lacunar hypothesis
Gan, R., Sacco, R. L., Kargman, D. E., Roberts, J. K., Boden-Albala, B. M., & Gu, Q. (1997) · Neurology · doi:10.1212/wnl.48.5.1204 · Cited by 189 · see citing works
Lesion Patterns and Stroke Mechanism in Atherosclerotic Middle Cerebral Artery Disease
Lee, D., Kim, J. S., Kwon, S. U., Yoo, S., & Kang, D. (2005) · Stroke · doi:10.1161/01.str.0000189999.19948.14 · Cited by 177 · see citing works
The fallacy of the lacune hypothesis.
Millikan, C. H., & Futrell, N. (1990) · Stroke · doi:10.1161/01.str.21.9.1251 · Cited by 177 · see citing works
Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia
Hutchinson, E. B., Stefanovic, B., Koretsky, A. P., & Silva, A. C. (2006) · NeuroImage · doi:10.1016/j.neuroimage.2006.03.033 · Cited by 127 · see citing works
Sustained decrease in brain regional blood flow after microsphere embolism in rats.
Miyake, K., Takeo, S., & Kaijihara, H. (1993) · Stroke · doi:10.1161/01.str.24.3.415 · Cited by 111 · see citing works
Cerebral Microcirculation in the Mouse Brain
Rosenblum, W. I. (1963) · Archives of Neurology · doi:10.1001/archneur.1963.00460100102012 · Cited by 111 · see citing works
Emboli enter penetrating arteries of monkey brain in relation to their size
Macdonald, R. L., Kowalczuk, A., & Johns, L. (1995) · Stroke · doi:10.1161/01.str.26.7.1247 · Cited by 91 · see citing works
The terminal vascular bed in the superficial cortex of the rat
Motti, E., Imhof, H.-G., & Yasargil, M. G. (1986) · Journal of neurosurgery · doi:10.3171/jns.1986.65.6.0834 · Cited by 90 · see citing works
Rovainen, C. M., Woolsey, T. A., Blocher, N. C., Wang, D.-B., & Robinson, O. F. (1993) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1993.49 · Cited by 79 · see citing works
In‐vivo confocal scanning laser microscopy of the cerebral microcirculation
Dirnagl, U., Villringer, A., & Einhäupl, K. M. (1992) · Journal of Microscopy · doi:10.1111/j.1365-2818.1992.tb04312.x · Cited by 75 · see citing works
A new method for the investigation of capillary structure
Tata, D. Α., & Anderson, B. J. (2002) · Journal of Neuroscience Methods · doi:10.1016/s0165-0270(01)00494-0 · Cited by 61 · see citing works
Mezzapesa, D. M., Rocca, M. A., Pagani, E., Comı, G., & Filippi, M. (2003) · Archives of Neurology · doi:10.1001/archneur.60.8.1109 · Cited by 30 · see citing works
An Experimental Model of Cerebral Microischemia in Rabbits
Roos, M. W., Sperber, G. O., Johansson, A., et al. (1996) · Experimental Neurology · doi:10.1006/exnr.1996.0008 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kozai, T. D. Y., Langhals, N. B., Patel, P. R., Deng, X., Zhang, H., Smith, K. L., Lahann, J., Kotov, N. A., & Kipke, D. R. (2012) · Nature Materials · doi:10.1038/nmat3468 · Cited by 721 · see citing works
The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow
Blinder, P., Tsai, P. S., Kaufhold, J. P., Knutsen, P. M., Suhl, H., & Kleinfeld, D. (2013) · Nature Neuroscience · doi:10.1038/nn.3426 · Cited by 573 · see citing works
Self-citationChronic optical access through a polished and reinforced thinned skull
Drew, P. J., Shih, A. Y., Driscoll, J. D., Knutsen, P. M., Blinder, P., Davalos, D., Akassoglou, K., Tsai, P. S., & Kleinfeld, D. (2010) · Nature Methods · doi:10.1038/nmeth.1530 · Cited by 406 · see citing works
Self-citationThe smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit
Shih, A. Y., Blinder, P., Tsai, P. S., Friedman, B., Stanley, G., Lyden, P. D., & Kleinfeld, D. (2013) · Nature Neuroscience · doi:10.1038/nn.3278 · Cited by 351 · see citing works
Self-citationVascular remodeling after ischemic stroke: mechanisms and therapeutic potentials.
Liu, J., Wang, Y., Akamatsu, Y., Lee, C. C., Stetler, R. A., Lawton, M. T., & Yang, G.-Y. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.11.004 · Cited by 335 · see citing works
Two-photon excitation microscopy for the study of living cells and tissues
Benninger, R. K. P., & Piston, D. W. (2013) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0411s59 · Cited by 311 · see citing works
The capillary bed offers the largest hemodynamic resistance to the cortical blood supply
Gould, I. G., Tsai, P., Kleinfeld, D., & Linninger, A. (2017) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16671146 · Cited by 252 · see citing works
Self-citationHainsworth, A. H., & Markus, H. S. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.91 · Cited by 240 · see citing works
Zhang, S., & Murphy, T. H. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050119 · Cited by 193 · see citing works
“In future studies it may be possible to use amplified laser pulses to clot individual deep vessels and create even more defined strokes that specifically model different components of stroke including hemorrhage and extravascation or block individual penetrating arteries that may form a bottleneck for local circulatio…”
Topological basis for the robust distribution of blood to rodent neocortex
Blinder, P., Shih, A. Y., Rafie, C., & Kleinfeld, D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1007239107 · Cited by 182 · see citing works
Self-citationTwo-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions
Kasischke, K. A., Lambert, E. M., Panepento, B., Sun, A., Gelbard, H. A., Burgess, R. W., Foster, T. H., & Nedergaard, M. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.158 · Cited by 160 · see citing works
Kozai, T. D. Y., Li, X., Bodily, L. M., Caparosa, E. M., Zenonos, G. A., Carlisle, D. L., Friedlander, R. M., & Cui, X. T. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.08.006 · Cited by 136 · see citing works
Shih, A. Y., Friedman, B., Drew, P. K., Tsai, P. S., Lyden, P. D., & Kleinfeld, D. (2009) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.166 · Cited by 127 · see citing works
Self-citationLimitations of collateral flow after occlusion of a single cortical penetrating arteriole
Nishimura, N., Rosidi, N. L., Iadecola, C., & Schaffer, C. B. (2010) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.157 · Cited by 117 · see citing works
Self-citationNguyen, J., Nishimura, N., Fetcho, R. N., Iadecola, C., & Schaffer, C. B. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2011.95 · Cited by 95 · see citing works
Self-citationRosidi, N. L., Zhou, J., Pattanaik, S., Wang, P., Jin, W., Brophy, M., Olbricht, W. L., Nishimura, N., & Schaffer, C. B. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026612 · Cited by 87 · see citing works
Self-citation
- Authors
- Nishimura, N., Schaffer, C. B., Friedman, B., Lyden, P. D., & Kleinfeld, D.
- Affiliations
- University of California San Diego (US)
- Neurosciences,
- Corresponding author
- Kleinfeld, David
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-01-02
- Volume
- 104
- Issue
- 1
- Pages
- 365-370
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1765467
- OpenAlex
- W2036472881
- Semantic Scholar
- a1b1bb2138e060c9e54834096ecb747911e5db00
- Cited by
- 367
- References
- 32
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 14 · 2023: 22 · 2022: 18 · 2021: 30 · 2020: 23 · 2019: 28 · 2018: 17 · 2017: 20 · 2016: 21 · 2015: 19 · 2014: 15 · 2013: 28 · 2012: 21
- FWCI
- 10.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS/043300, R01NS043300)
- National Institute of Biomedical Imaging and Bioengineering (R01EB003832, EB/003832)
- National Center for Research Resources (RR/021907, R21RR021907)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- penetrating arterioles, cerebral blood flow, arteriolar occlusion, ischemia, red blood cell flow, microvascular bed, parietal cortex, two-photon microscopy, cerebral microcirculation
- MeSH terms
- Animals, Arterioles, Brain Ischemia, Cerebrovascular Circulation, Humans, Male, Models, Cardiovascular, Perfusion, Rats, Sprague-Dawley, Neocortex, Stroke, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review