A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures
Open accessAbstract
BACKGROUND: Myeloid cells have been associated with physiological and pathological angiogenesis, but their exact functions in these processes remain poorly defined. Monocyte-derived tissue macrophages of the CNS, or microglial cells, invade the mammalian retina before it becomes vascularized. Recent studies correlate the presence of microglia in the developing CNS with vascular network formation, but it is not clear whether the effect is directly caused by microglia and their contact with the endothelium. METHODOLOGY/PRINCIPAL FINDINGS: We combined in vivo studies of the developing mouse retina with in vitro studies using the aortic ring model to address the role of microglia in developmental angiogenesis. Our in vivo analyses are consistent with previous findings that microglia are present at sites of endothelial tip-cell anastomosis, and genetic ablation of microglia caused a sparser vascular network associated with reduced number of filopodia-bearing sprouts. Addition of microglia in the aortic ring model was sufficient to stimulate vessel sprouting. The effect was independent of physical contact between microglia and endothelial cells, and could be partly mimicked using microglial cell-conditioned medium. Addition of VEGF-A promoted angiogenic sprouts of different morphology in comparison with the microglial cells, and inhibition of VEGF-A did not affect the microglia-induced angiogenic response, arguing that the proangiogenic factor(s) released by microglia is distinct from VEGF-A. Finally, microglia exhibited oriented migration towards the vessels in the aortic ring cultures. CONCLUSIONS/SIGNIFICANCE: Microglia stimulate vessel sprouting in the aortic ring cultures via a soluble microglial-derived product(s), rather than direct contact with endothelial cells. The observed migration of microglia towards the growing sprouts suggests that their position near endothelial tip-cells could result from attractive cues secreted by the vessels. Our data reveals a two-way communication between microglia and vessels that depends on soluble factors and should extend the understanding of how microglia promote vascular network formation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Microglia associate with endothelial tip cells during embryonic brain and postnatal retinal angiogenesis.
“microglia associate with endothelial tip cells, as demonstrated during embryonic brain and postnatal retinal angiogenesis”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Rymo et al., 2011
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Angiogenesis in life, disease and medicine
Carmeliet, P. (2005) · Nature · doi:10.1038/nature04478 · Cited by 3,494 · see citing works
VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia
Gerhardt, H., Golding, M., Fruttiger, M., Ruhrberg, C., Lundkvist, A., Abramsson, A., Jeltsch, M., Mitchell, C., Alitalo, K., Shima, D., et al. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200302047 · Cited by 2,894 · see citing works
Self-citationYoshida, H., Hayashi, S.-I., Kunisada, T., Ogawa, M., Nishikawa, S., Okamura, H., Sudo, T., Shultz, L. D., & Nishikawa, S.-I. (1990) · Nature · doi:10.1038/345442a0 · Cited by 1,789 · see citing works
Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis
Hellström, M., Phng, L.-K., Hofmann, J. J., Wallgard, E., Coultas, L., Lindblom, P., Alva, J., Nilsson, A.-K., Karlsson, L., Gaiano, N., et al. (2007) · Nature · doi:10.1038/nature05571 · Cited by 1,775 · see citing works
Self-citationEremina, V., Sood, M. M., Haigh, J. J., Nagy, A., Lajoie, G., Ferrara, N., Gerber, H. P., Kikkawa, Y., Miner, J. H., & Quaggin, S. E. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17423 · Cited by 1,308 · see citing works
Fantin, A., Vieira, J. M., Gestri, G., Denti, L., Schwarz, Q., Prykhozhij, S., Peri, F., Wilson, S. W., & Ruhrberg, C. (2010) · Blood · doi:10.1182/blood-2009-12-257832 · Cited by 1,153 · see citing works
Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities
McKercher, S. R., Torbett, B. E., Anderson, K. L., Henkel, G. W., Vestal, D. J., Baribault, H., Klemsz, M., Feeney, A. J., Wu, G. E., Paige, C. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00949.x · Cited by 1,130 · see citing works
VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells
Grunewald, M., Avraham, I., Dor, Y., Bachar-Lustig, E., Itin, A., Yung, S., Chimenti, S., Landsman, L., Abramovitch, R., & Keshet, E. (2006) · Cell · doi:10.1016/j.cell.2005.10.036 · Cited by 1,125 · see citing works
Luttun, A., Tjwa, M., Moons, L., Wu, Y. L., Angelillo‐Scherrer, A., Liao, F., Nagy, J. A., Hooper, A. T., Priller, J., Klerck, B. D., et al. (2002) · Nature Medicine · doi:10.1038/nm731 · Cited by 1,067 · see citing works
Stone, J., Itin, A., Alon, T., Pe'er, J., Gnessin, H., Chan‐Ling, T., & Keshet, E. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-07-04738.1995 · Cited by 1,004 · see citing works
Perry, V. H., Hume, D. A., & Gordon, S. (1985) · Neuroscience · doi:10.1016/0306-4522(85)90215-5 · Cited by 902 · see citing works
Suchting, S., Freitas, C., le Noble, F. A. C., Benedito, R., Bréant, C., Duarte, A., & Eichmann, A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611177104 · Cited by 812 · see citing works
Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting
Lobov, I. B., Renard, R. A., Papadopoulos, N., Gale, N. W., Thurston, G., Yancopoulos, G. D., & Wiegand, S. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611206104 · Cited by 775 · see citing works
Macrophages and microglia in the nervous system
Perry, V. H., & Gordon, S. (1988) · Trends in Neurosciences · doi:10.1016/0166-2236(88)90110-5 · Cited by 747 · see citing works
Microglia: biology and pathology
Graeber, M. B., & Streit, W. J. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0622-0 · Cited by 720 · see citing works
Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries
Siekmann, A. F., & Lawson, N. D. (2007) · Nature · doi:10.1038/nature05577 · Cited by 689 · see citing works
Nicosia, R. F., & Ottinetti, A. (1990) · PubMed · Cited by 595 · see citing works
Macrophage Depletion Inhibits Experimental Choroidal Neovascularization
Sakurai, E., Anand, A., Ambati, B. K., van Rooijen, N., & Ambati, J. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.03-0097 · Cited by 498 · see citing works
Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis
Stockmann, C., Doedens, A. L., Weidemann, A., Zhang, N., Takeda, N., Greenberg, J. I., Cheresh, D. A., & Johnson, R. S. (2008) · Nature · doi:10.1038/nature07445 · Cited by 473 · see citing works
Tumor-Associated Macrophages Press the Angiogenic Switch in Breast Cancer
Lin, E. Y., & Pollard, J. W. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0912 · Cited by 463 · see citing works
Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis
Leslie, J. D., Ariza‐McNaughton, L., Bermange, A. L., Mcadow, R., Johnson, S. L., & Lewis, J. H. (2007) · Development · doi:10.1242/dev.003244 · Cited by 415 · see citing works
Espinosa‐Heidmann, D. G., Suñer, I. J., Hernandez, E. P., Monroy, D. C., Csaky, K. G., & Cousins, S. W. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.03-0038 · Cited by 401 · see citing works
M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis
Kubota, Y., Takubo, K., Shimizu, T., Ohno, H., Kishi, K., Shibuya, M., Saya, H., & Suda, T. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20081605 · Cited by 388 · see citing works
Potential Role of Microglia in Retinal Blood Vessel Formation
Checchin, D., Sennlaub, F., Levavasseur, E., Leduc, M., & Chemtob, S. (2006) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.05-1522 · Cited by 369 · see citing works
VEGFR-1–Selective VEGF Homologue PlGF Is Arteriogenic
Pipp, F. C., Heil, M., Issbrücker, K., Ziegelhoeffer, T., Martin, S. M., van den Heuvel, J., Weich, H. A., Fernández, B., Golomb, G., Carmeliet, P., et al. (2003) · Circulation Research · doi:10.1161/01.res.0000057997.77714.72 · Cited by 315 · see citing works
Relationship between astrocytes, ganglion cells and vasculature of the retina
Stone, J., & Dreher, Z. (1987) · The Journal of Comparative Neurology · doi:10.1002/cne.902550104 · Cited by 298 · see citing works
Mitchell, P. L. R., Jf, K., Lanzetta, P., Holz, F. G., Prünte, C. F., Schmidt-Erfurth, U. M., Tano, Y., & Wolf, S. (2009) · British Journal of Ophthalmology · doi:10.1136/bjo.2009.159160 · Cited by 297 · see citing works
The microglial cell. A historical review
Barron, K. D. (1995) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(95)00209-k · Cited by 279 · see citing works
Neuropilin‐1 is required for endothelial tip cell guidance in the developing central nervous system
Gerhardt, H., Ruhrberg, C., Abramsson, A., Fujisawa, H., Shima, D. T., & Betsholtz, C. (2004) · Developmental Dynamics · doi:10.1002/dvdy.20148 · Cited by 268 · see citing works
Self-citationBrain macrophages: questions of origin and interrelationship
Jordan, F. L., & Thomas, W. E. (1988) · Brain Research Reviews · doi:10.1016/0165-0173(88)90019-7 · Cited by 222 · see citing works
(2010) · Chapman & Hall/CRC finance series · doi:10.1201/b10338-4 · Cited by 203 · see citing works
Myeloid Development Is Selectively Disrupted in PU.1 Null Mice
Anderson, K. L., Smith, K. A., Conners, K., McKercher, S. R., Maki, R. A., & Torbett, B. E. (1998) · Blood · doi:10.1182/blood.v91.10.3702 · Cited by 193 · see citing works
VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration
Dixon, J. A., Oliver, S. C. N., Olson, J. L., & Mandava, N. (2009) · Expert Opinion on Investigational Drugs · doi:10.1517/13543780903201684 · Cited by 134 · see citing works
The aortic ring model of angiogenesis: a quarter century of search and discovery
Nicosia, R. F. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00891.x · Cited by 130 · see citing works
Chapter 7 The Aortic Ring Model of Angiogenesis
Aplin, A. C., Fogel, E., Zorzi, P., & Nicosia, R. F. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)02007-7 · Cited by 116 · see citing works
The Angiogenic Response of the Aorta to Injury and Inflammatory Cytokines Requires Macrophages
Gelati, M., Aplin, A. C., Fogel, E., Smith, K. D., & Nicosia, R. F. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5711 · Cited by 44 · see citing works
Zorzi, P., Aplin, A. C., Smith, K. D., et al. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0310178 · Cited by 34 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The impact of microglial activation on blood-brain barrier in brain diseases
da Fonseca, A. C. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., & Lima, F. R. S. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00362 · Cited by 572 · see citing works
The Indispensable Roles of Microglia and Astrocytes during Brain Development
Reemst, K., Noctor, S. C., Lucassen, P. J., & Hol, E. M. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00566 · Cited by 516 · see citing works
Macrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis
Corliss, B. A., Azimi, M. S., Munson, J. M., Peirce, S. M., & Murfee, W. L. (2016) · Microcirculation · doi:10.1111/micc.12259 · Cited by 356 · see citing works
Microglia–blood vessel interactions: a double-edged sword in brain pathologies
Dudvarski Stankovic, N., Teodorczyk, M., Ploen, R., Zipp, F., & Schmidt, M. H. H. (2016) · Acta Neuropathologica · doi:10.1007/s00401-015-1524-y · Cited by 301 · see citing works
Microglia in the developing brain: a potential target with lifetime effects
Harry, G. J., & Kraft, A. D. (2012) · NeuroToxicology · doi:10.1016/j.neuro.2012.01.012 · Cited by 250 · see citing works
Notch signaling in developmental and tumor angiogenesis
Kofler, N. M., Shawber, C. J., Kangsamaksin, T., Reed, H. O., Galatioto, J., & Kitajewski, J. (2011) · Genes & Cancer · doi:10.1177/1947601911423030 · Cited by 142 · see citing works
The microglia in healthy and diseased retina
Li, L., Eter, N., & Heiduschka, P. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.04.020 · Cited by 112 · see citing works
Inflammation within the neurovascular unit: Focus on microglia for stroke injury and recovery
Eldahshan, W., Fagan, S. C., & Ergul, A. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104349 · Cited by 104 · see citing works
- Authors
- Rymo, S. F., Gerhardt, H., Wolfhagen Sand, F., Lang, R., Uv, A., & Betsholtz, C.
- Affiliations
- University of Gothenburg (SE)
- Cancer Research UK (GB)
- Cincinnati Children's Hospital Medical Center (US)
- Karolinska Institutet (SE)
- Corresponding author
- Betsholtz, Christer
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-01-10
- Volume
- 6
- Issue
- 1
- Pages
- e15846
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3018482
- OpenAlex
- W2019678208
- Cited by
- 235
- References
- 37
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 16 · 2023: 16 · 2022: 16 · 2021: 20 · 2020: 15 · 2019: 18 · 2018: 19 · 2017: 23 · 2016: 18 · 2015: 14 · 2014: 13 · 2013: 14 · 2012: 14
- FWCI
- 6.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- Ludwig Institute for Cancer Research
- Swedish Cancer Foundation
- Cancer Research UK
- Lister Institute of Preventive Medicine
- Fondation Leducq
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- National Institutes of Health
- National Eye Institute
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- microglia, angiogenesis, vessel sprouting, aortic ring assay, retinal vascular development, VEGF-A, microglial migration, tip cells, myeloid cells, soluble factors
- MeSH terms
- Aorta, Cell Communication, Cells, Cultured, Endothelium, Vascular, Pseudopodia, Retina, Culture Media, Conditioned, Microglia, Neovascularization, Physiologic, Cell Shape
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
