Thrombospondin-1 modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina
Open accessAbstract
Microvascular development is often perceived to result from a balance of positive and negative factors that impact signaling for proliferation and survival. The survival signaling that results from hypoxia-induced VEGF-A has been well established, but the factors that antagonize this signaling have been poorly studied. As endogenous inhibitors of angiogenesis, thrombospondins (TSPs) are likely candidates to affect survival signaling. Here we report that TSP1 antagonized microvascular survival to retinal hyperoxia, and Akt signaling in both the retina and in cultured endothelial cells. TSP1 expression is correlated with the association of the CD36 receptor with Src versus Fyn. In the presence of TSP1, CD36 is coprecipitated with Fyn as previously shown by others. However, in the absence of TSP1, there is a preferential association with Src. We now demonstrate that these Src family kinases play an important role in modulating microvascular survival in response to TSP1 by crossing tsp1(-/-) mice to the src(-/-) and fyn(-/-) mice and testing the survival of retinal blood vessels in hyperoxia. We find that tsp1(-/-), fyn(-/-), and double-mutant tsp1(-/-)/fyn(-/-) mice have a similar enhancement of capillary survival in oxygen, whereas in a tsp(-/-) background, the loss of only one allele of src restores the balance in survival and apoptosis to that of wild-type mice. Taken together, we hypothesize that TSP1 antagonizes VEGF-driven Akt survival signaling in part through the recruitment of Fyn to membrane domains containing CD36, but when TSP1 is absent, an opposing Src recruitment contributes to VEGF-driven Akt phosphorylation and capillary survival.
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FRK has been shown to have negative function on the stimulation of microvascular survival of the developing retina by mediating downstream signaling of thrombospondin-1 and the thrombospondin receptor (CD36), which antagonizes VEGFA signaling of the Akt pathway.
“FRK has also been shown to have negative function on the stimulation of microvascular survival of the developing retina by mediating the downstream signaling of thrombospondin-1 and the thrombospondin receptor (CD36), which has been shown to antagonize VEGFA signaling of the Akt pathway (32).”
From Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration (2011) · cites this paper as [32]
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Cites
Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis
Shweiki, D., Itin, A., Soffer, D., & Keshet, E. (1992) · Nature · doi:10.1038/359843a0 · Cited by 4,617 · see citing works
Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
Forsythe, J. A., Jiang, B.-H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., & Semenza, G. L. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4604 · Cited by 3,981 · see citing works
Regulation of endothelium-derived nitric oxide production by the protein kinase Akt
Fulton, D. J., Gratton, J., McCabe, T. J. D., Fontana, J. T., Fujio, Y., Walsh, K. X., Franke, T. F., Papapetropoulos, A., & Sessa, W. C. (1999) · Nature · doi:10.1038/21218 · Cited by 2,585 · see citing works
Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Christopherson, K. S., Ullian, E. M., Stokes, C. C. A., Mullowney, C. E., Hell, J. W., Agah, A., Lawler, J., Mosher, D. F., Bornstein, P., & Barres, B. A. (2005) · Cell · doi:10.1016/j.cell.2004.12.020 · Cited by 1,688 · see citing works
Self-citationOxygen-induced retinopathy in the mouse.
Smith, L. E. H., Wesolowski, E., McLellan, A., Kostyk, S. K., D’Amato, R. J., Sullivan, R., & D'Amore, P. A. (1994) · PubMed · Cited by 1,627 · see citing works
Alon, T., Hemo, I., Itin, A., Pe’er, J., Stone, J., & Keshet, E. (1995) · Nature Medicine · doi:10.1038/nm1095-1024 · Cited by 1,605 · see citing works
Benjamin, L. E., Hemo, I., & Keshet, E. (1998) · Development · doi:10.1242/dev.125.9.1591 · Cited by 1,265 · see citing works
Self-citationSignals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1
Jiménez, B., Volpert, O. V., Crawford, S. E., Febbraio, M., Silverstein, R. L., & Bouck, N. (2000) · Nature Medicine · doi:10.1038/71517 · Cited by 1,014 · 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
Selective Requirement for Src Kinases during VEGF-Induced Angiogenesis and Vascular Permeability
Eliceiri, B. P., Paul, R., Schwartzberg, P. L., Hood, J. D., Leng, J., & Cheresh, D. A. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80221-x · Cited by 814 · see citing works
CD36 Mediates the In Vitro Inhibitory Effects of Thrombospondin-1 on Endothelial Cells
Dawson, D. W., Pearce, S. F. A., Zhong, R., Silverstein, R. L., Frazier, W. A., & Bouck, N. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.138.3.707 · Cited by 676 · see citing works
Thrombospondin‐1 as an endogenous inhibitor of angiogenesis and tumor growth
Lawler, J. (2002) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2002.tb00307.x · Cited by 541 · see citing works
Self-citationStein, I., Itin, A., Einat, P., Skaliter, R., Grossman, Z., & Keshet, E. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.6.3112 · Cited by 498 · see citing works
Rodrı́guez-Manzaneque, J. C., Lane, T. F., Ortega, M.-A., Hynes, R. O., Lawler, J., & Iruela‐Arispe, M. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171460498 · Cited by 473 · see citing works
Self-citationThe functions of thrombospondin-1 and-2
Lawler, J. (2000) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00143-5 · Cited by 441 · see citing works
Self-citationPathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin
Phung, T. L., Ziv, K., Dabydeen, D. A., Eyiah-Mensah, G., Riveros, M., Perruzzi, C. A., Sun, J., Monahan-Earley, R. A., Shiojima, I., Nagy, J. A., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.07.003 · Cited by 439 · see citing works
Self-citationHuang, M., Bolen, J. B., Barnwell, J. W., Shattil, S. J., & Brugge, J. S. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.17.7844 · Cited by 406 · see citing works
The cell biology of thrombospondin-1
Chen, H., Herndon, M. E., & Lawler, J. (2000) · Matrix Biology · doi:10.1016/s0945-053x(00)00107-4 · Cited by 393 · see citing works
Self-citationHaynes, M. P., Li, L., Sinha, D., Russell, K. S., Hisamoto, K., Baron, R., Collinge, M., Sessa, W. C., & Bender, J. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210828200 · Cited by 305 · see citing works
Guo, N., Krutzsch, H. C., Inman, J. K., & Roberts, D. D. (1997) · PubMed · Cited by 293 · see citing works
Majack, R. A., Cook, S. C., & BORNSTEIN, P. K. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.23.9050 · Cited by 256 · see citing works
Self-citationThrombospondin 2, a matricellular protein with diverse functions
BORNSTEIN, P. K., Armstrong, L. C., Hankenson, K. D., Kyriakides, T. R., & Yang, Z. (2000) · Matrix Biology · doi:10.1016/s0945-053x(00)00104-9 · Cited by 171 · see citing works
Self-citationBucci, M., Roviezzo, F., Posadas, I., Yu, J., Parente, L., Sessa, W. C., Ignarro, L. J., & Cirino, G. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408906102 · Cited by 140 · see citing works
Microvascular patterning is controlled by fine-tuning the Akt signal
Sun, J. F., Phung, T. L., Shiojima, I., Felske, T., Upalakalin, J. N., Feng, D., Kornaga, T., Dor, T., Dvořàk, A. M., Walsh, K., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403198102 · Cited by 139 · see citing works
Self-citationShort, S. M., Derrien, A., Narsimhan, R. P., Lawler, J., Ingber, D. E., & Zetter, B. R. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200407060 · Cited by 137 · see citing works
Self-citationThrombospondin-1 Inhibits Nitric Oxide Signaling via CD36 by Inhibiting Myristic Acid Uptake
Isenberg, J. S., Jia, Y., Fukuyama, J., Switzer, C., Wink, D. A., & Roberts, D. D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701638200 · Cited by 137 · see citing works
Richard, L., Velasco, P., & Detmar, M. J. (1998) · Experimental Cell Research · doi:10.1006/excr.1998.3936 · Cited by 134 · see citing works
Wang, S., Wu, Z., Sorenson, C. M., Lawler, J., & Sheibani, N. (2003) · Developmental Dynamics · doi:10.1002/dvdy.10412 · Cited by 133 · see citing works
Self-citationThrombospondin modules and angiogenesis
Iruela‐Arispe, M. L., Luque, A., & Lee, N. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.01.025 · Cited by 122 · see citing works
Simantov, R., Febbraio, M., & Silverstein, R. L. (2004) · Matrix Biology · doi:10.1016/j.matbio.2004.11.005 · Cited by 121 · see citing works
Miao, W., Seng, W. L., Duquette, M. A., Lawler, P. R., Laus, C., & Lawler, J. (2001) · PubMed · Cited by 118 · see citing works
Self-citationAdams, J. C. (1997) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(96)00171-9 · Cited by 111 · see citing works
Endothelial nitric oxide synthase regulates microvascular hyperpermeability in vivo
Hatakeyama, T., Pappas, P. J., Hobson, R. W., Borić, M. P., Sessa, W. C., & Durán, W. N. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108175 · Cited by 110 · see citing works
CD36 associates with CD9 and integrins on human blood platelets
Miao, W., Vasile, E., Lane, W. S., et al. (2001) · Blood · doi:10.1182/blood.v97.6.1689 · Cited by 107 · see citing works
Bull, H. A., Brickell, P. M., & Dowd, P. M. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00814-0 · Cited by 105 · see citing works
Calzada, M. J., Annis, D. S., Zeng, B., Marcinkiewicz, C., Banas, B., Lawler, J., Mosher, D. F., & Roberts, D. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406267200 · Cited by 96 · see citing works
Self-citationIdentification of CD36 molecular features required for its in vitro angiostatic activity
Primo, L., Ferrandi, C., Roca, C., Marchiò, S., di Blasio, L., Alessio, M., & Bussolino, F. (2005) · The FASEB Journal · doi:10.1096/fj.05-3697fje · Cited by 78 · see citing works
Oganesian, A., Armstrong, L. C., Migliorini, M. M., Strickland, D. K., & BORNSTEIN, P. K. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-07-0649 · Cited by 72 · see citing works
Self-citationWu, Z., Wang, S., Sorenson, C. M., & Sheibani, N. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20837 · Cited by 39 · see citing works
The association between CD36 and Lyn protein tyrosine kinase is mediated by lipid
Thorne, R. F., Law, E. G., Elith, C. A., Ralston, K. J., Bates, R. C., & Burns, G. F. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.09.156 · Cited by 28 · see citing works
Oxygen-Induced Retinopathy in the Rat
Penn, J. S., & Thum, L. A. (1988) · Springer eBooks · doi:10.1007/978-1-4684-5568-7_168 · Cited by 21 · see citing works
Survival Mechanisms of VEGF and PlGF during Microvascular RemodelingPreprint
Upalakalin, J. N., Hemo, I., Dehio, C., et al. (2002) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2002.67.181 · Cited by 11 · see citing works
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Yu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., Souied, E. H., Richardson, A. J., Merriam, J. E., Buitendijk, G. H. S., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr270 · Cited by 254 · see citing works
“FRK has also been shown to have negative function on the stimulation of microvascular survival of the developing retina by mediating the downstream signaling of thrombospondin-1 and the thrombospondin receptor (CD36), which has been shown to antagonize VEGFA signaling of the Akt pathway (32).”
BackgroundThrombospondin-1 inhibits VEGF receptor-2 signaling by disrupting its association with CD47
Kaur, S., Martin-Manso, G., Pendrak, M. L., Garfield, S. H., Isenberg, J. S., & Roberts, D. D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.172304 · Cited by 235 · see citing works
- Authors
- Sun, J., Hopkins, B. D., Tsujikawa, K., Perruzzi, C., Adini, I., Swerlick, R., Bornstein, P., Lawler, J., & Benjamin, L. E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2009-05
- Volume
- 296
- Issue
- 5
- Pages
- H1344-H1351
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC2685346
- OpenAlex
- W2039914069
- Cited by
- 56
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 5
- FWCI
- 2.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL071049, HL71049)
- National Cancer Institute (P01CA092644, CA-092644)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- thrombospondin-1, VEGF-A, Akt signaling, CD36, Src family kinases, Fyn, Src kinase, angiogenesis inhibition, endothelial cell survival, apoptosis, hypoxia
- MeSH terms
- Thrombospondin 2, Animals, Animals, Newborn, Capillaries, Cell Survival, Cells, Cultured, Disease Models, Animal, Humans, Oxygen, Phosphorylation, Retina, Retinal Vessels, Time Factors, Signal Transduction, Apoptosis, Mice, Knockout, Hyperoxia, Neovascularization, Physiologic, CD36 Antigens, src-Family Kinases, Thrombospondins, Thrombospondin 1, Vascular Endothelial Growth Factor A, Endothelial Cells, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-fyn, Mice
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