The microenvironment for erythropoiesis is regulated by HIF-2α through VCAM-1 in endothelial cells
Open accessAbstract
Erythropoiesis is a dynamic process regulated by oxygen in vertebrates. Recent evidence has indicated that erythropoietin (Epo) expression is regulated by hypoxia-inducible transcription factors (HIFs), HIF-2alpha in particular. In this study, we report that knockdown mutation of HIF-2alpha in mice (kd/kd) results in normocytic anemia, despite Epo induction in response to hypoxia not being severely affected. Transplantation analyses clearly demonstrated that the hematopoietic microenvironment, but not the hematopoietic cells, was altered in kd/kd. Furthermore, cell-type specific recovery of HIF-2alpha expression in endothelial cells (ECs) abrogated the anemic condition of the kd/kd mice, indicating that HIF-2alpha in EC plays an essential role in supporting erythropoiesis. In the absence of HIF-2alpha, the expression of vascular adhesion molecule-1 (VCAM-1) was reduced significantly and restoration of VCAM-1 expression in kd/kd ECs enhanced the development of erythroid progenitors. Finally, a chromatin immunoprecipitation assay and a reporter assay indicated that VCAM-1 gene transcription is directly regulated by HIF-2alpha. These data suggest that the hematopoietic microenvironment required for erythropoiesis is dynamically regulated by oxygen through the functions of HIF-2alpha in ECs.
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?
Hypoxia promotes erythropoiesis by modulating erythroid progenitor maturation and proliferation.
“It promotes erythropoiesis by modulating erythroid progenitor maturation and proliferation.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [225]
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
Purification and Characterization of Hypoxia-inducible Factor 1
Wang, G. L., & Semenza, G. L. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.3.1230 · Cited by 2,069 · see citing works
Tian, H., McKnight, S. L., & Russell, D. W. (1997) · Genes & Development · doi:10.1101/gad.11.1.72 · Cited by 1,351 · see citing works
Wu, H., Liu, X., Jaenisch, R., & Lodish, H. F. (1995) · Cell · doi:10.1016/0092-8674(95)90234-1 · Cited by 1,007 · see citing works
Wang, G., & Semenza, G. (1993) · Blood · doi:10.1182/blood.v82.12.3610.3610 · Cited by 766 · see citing works
Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W., & McKnight, S. L. (1998) · Genes & Development · doi:10.1101/gad.12.21.3320 · Cited by 647 · see citing works
Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo
Rankin, E. B., Biju, M. P., Liu, Q., Unger, T. L., Rha, J., Johnson, R. S., Simon, M. C., Keith, B., & Haase, V. H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30117 · Cited by 596 · see citing works
Gu, Y.-Z., Moran, S. M., Hogenesch, J. B., Wartman, L. D., & Bradfield, C. A. (1998) · Europe PMC (PubMed Central) · Cited by 577 · see citing works
Scortegagna, M., Ding, K., Oktay, Y., Gaur, A., Thurmond, F., Yan, L.-J., Marck, B. T., Matsumoto, A. M., Shelton, J. M., Richardson, J. A., et al. (2003) · Nature Genetics · doi:10.1038/ng1266 · Cited by 496 · see citing works
Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization
Koury, S., Bondurant, M. C., & Koury, M. (1988) · Blood · doi:10.1182/blood.v71.2.524.524 · Cited by 469 · see citing works
Peng, J., Zhang, L., Drysdale, L., & Fong, G.-H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.140087397 · Cited by 460 · see citing works
Acute postnatal ablation of <i>Hif-2</i> α results in anemia
Gruber, M., Hu, C.-J., Johnson, R. S., Brown, E. J., Keith, B., & Simon, M. C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0608382104 · Cited by 457 · see citing works
Lin, C. S., Lim, S. K., D’Agati, V. D., & Costantini, F. D. (1996) · Genes & Development · doi:10.1101/gad.10.2.154 · Cited by 419 · see citing works
Identification of the renal erythropoietin-producing cells using transgenic mice
Maxwell, P. H., Osmond, M. K., Pugh, C. W., Heryet, A. R., Nicholls, L. G., Tan, C. C., Doe, B., Ferguson, D. J. P., Johnson, M. H., & Ratcliffe, P. J. (1993) · Kidney International · doi:10.1038/ki.1993.362 · Cited by 388 · see citing works
Zhang, J., Socolovsky, M., Gross, A. W., & Lodish, H. F. (2003) · Blood · doi:10.1182/blood-2003-05-1479 · Cited by 386 · see citing works
Miyake, K., Medina, K. L., Ishihara, K., Kimoto, M., Auerbach, R., & Kincade, P. W. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.114.3.557 · Cited by 381 · see citing works
Erythropoietin after a century of research: younger than ever
JELKMANN, W. E. B. (2007) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2007.00818.x · Cited by 365 · see citing works
Semenza, G. L., Koury, S. T., Nejfelt, M. K., Gearhart, J. D., & Antonarakis, S. E. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.19.8725 · Cited by 248 · see citing works
HIF-2α regulates murine hematopoietic development in an erythropoietin-dependent manner
Scortegagna, M., Ding, K., Zhang, Q., Oktay, Y., Bennett, M. J., Bennett, M., Shelton, J. M., Richardson, J. A., Moe, O. W., & Garcia, J. A. (2004) · Blood · doi:10.1182/blood-2004-05-1695 · Cited by 233 · see citing works
HLF/HIF‐2α is a key factor in retinopathy of prematurity in association with erythropoietin
Morita, M., Ohneda, O., Yamashita, T., Takahashi, S., Suzuki, N., Nakajima, O., Kawauchi, S., Ema, M., Shibahara, S., Udono, T., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg117 · Cited by 230 · see citing works
Self-citationKappel, A., Rönicke, V., Damert, A., Flamme, I., Risau, W., & Breier, G. (1999) · Blood · doi:10.1182/blood.v93.12.4284 · Cited by 223 · see citing works
Repression via the GATA box is essential for tissue-specific erythropoietin gene expression
Obara, N., Suzuki, N., Kim, K., Nagasawa, T., Imagawa, S., & Yamamoto, M. P. (2008) · Blood · doi:10.1182/blood-2007-10-115857 · Cited by 206 · see citing works
Li, H., Cybulsky, M. I., Gimbrone, M. A., & Libby, P. (1993) · PubMed Central · Cited by 203 · see citing works
The HIF family member EPAS1/HIF-2α is required for normal hematopoiesis in mice
Scortegagna, M., Morris, M. A., Oktay, Y., Bennett, M., & Garcia, J. A. (2003) · Blood · doi:10.1182/blood-2003-02-0448 · Cited by 203 · see citing works
Adhesion Receptors as Regulators of the Hematopoietic Process
Verfaillie, C. M. (1998) · Blood · doi:10.1182/blood.v92.8.2609 · Cited by 200 · see citing works
Kappel, A., Rönicke, V., Damert, A., et al. (1999) · Blood · doi:10.1182/blood.v93.12.4284.412k25_4284_4292 · Cited by 183 · see citing works
Trentin, J. J. (1971) · PubMed · Cited by 173 · see citing works
Regulation of Hematopoiesis by Microvascular Endothelium
Rafii, S., Möhle, R., Shapiro, F., Frey, B. M., & Moore, M. A. S. (1997) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428199709058305 · Cited by 169 · see citing works
Leavesley, D. I., Oliver, J. M., Swart, B., et al. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.10.4673 · Cited by 160 · see citing works
Stem cell homing: Rolling, crawling, and nesting
Quesenberry, P. J., & Becker, P. S. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15155 · Cited by 159 · see citing works
ALCAM (CD166): its role in hematopoietic and endothelial development
Ohneda, O., Ohneda, K., Arai, F., et al. (2001) · Blood · doi:10.1182/blood.v98.7.2134 · Cited by 158 · see citing works
Self-citationGustafsson, E., Brakebusch, C., Hietanen, K., & Fässler, R. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.4.671 · Cited by 149 · see citing works
Ohneda, O., Fennie, C., Zheng, Z., et al. (1998) · Blood · doi:10.1182/blood.v92.3.908 · Cited by 140 · see citing works
Self-citationNagano, M., Yamashita, T., Hamada, H., Ohneda, K., Kimura, K., Nakagawa, T., Shibuya, M., Yoshikawa, H., & Ohneda, O. (2007) · Blood · doi:10.1182/blood-2006-10-047092 · Cited by 133 · see citing works
Self-citationYamashita, T., Ohneda, O., Nagano, M., Iemitsu, M., Makino, Y., Tanaka, H., Miyauchi, T., Goto, K., Ohneda, K., Fujii‐Kuriyama, Y., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01332-07 · Cited by 115 · see citing works
Self-citationDefinitive hematopoietic commitment within the embryonic vascular endothelial-cadherin+ population
Fraser, S. T., Ogawa, M., Yu, R. T., et al. (2002) · Experimental Hematology · doi:10.1016/s0301-472x(02)00887-1 · Cited by 105 · see citing works
Roles for integrin very late activation antigen-4 in stroma-dependent erythropoiesis
Yanai, N., Sekine, C., Yagita∥, H., et al. (1994) · Blood · doi:10.1182/blood.v83.10.2844.2844 · Cited by 104 · see citing works
Integrin expression profiles during erythroid differentiation
Papayannopoulou, T., & Brice, M. C. (1992) · Blood · doi:10.1182/blood.v79.7.1686.1686 · Cited by 87 · see citing works
Ye, Z. Q., Burkholder, J. K., Qiu, P., et al. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.25.12140 · Cited by 72 · see citing works
Hemopoietic progenitor cell binding to the stromal microenvironment in vitro.
Gordon, M. Y., Clarke, D., Atkinson, J., et al. (1990) · PubMed · Cited by 68 · see citing works
A critical role of VLA-4 in erythropoiesis in vivo
Hamamura, K., Matsuda, H., Takeuchi, Y., Habu, S., Yagita∥, H., & Okumura, K. (1996) · Blood · doi:10.1182/blood.v87.6.2513.bloodjournal8762513 · Cited by 67 · see citing works
Endothelium-Intrinsic Requirement for Hif-2 α During Vascular Development
Duan, L., Zhang‐Benoit, Y., & Fong, G. (2005) · Circulation · doi:10.1161/01.cir.0000163580.98098.a3 · Cited by 60 · see citing works
Spleen stromal cell lines selectively support erythroid colony formation
Yanai, N., Matsuya, Y., & Obinata, M. (1989) · Blood · doi:10.1182/blood.v74.7.2391.2391 · Cited by 50 · see citing works
Ohneda, O., Yanai, N., & Obinata, M. (1990) · Development · doi:10.1242/dev.110.2.379 · Cited by 39 · see citing works
Self-citationKameoka, J.-I., Yanai, N., & Obinata, M. (1995) · Journal of Cellular Physiology · doi:10.1002/jcp.1041640108 · Cited by 39 · see citing works
The erythropoietin gene is expressed strongly in the mammalian mesonephric kidney
Wintour, E. M., Butkus, A., Earnest, L., et al. (1996) · Blood · doi:10.1182/blood.v88.9.3349.bloodjournal8893349 · Cited by 25 · see citing works
Suzuki, M., Ohneda, K., Hosoya-Ohmura, S., et al. (2006) · Blood · doi:10.1182/blood-2005-10-4064 · Cited by 22 · see citing works
Self-citationCombined action of c-Kit and erythropoietin on erythroid progenitor cells
Ohneda, O., Yanai, N., & Obinata, M. (1992) · Development · doi:10.1242/dev.114.1.245 · Cited by 19 · see citing works
Self-citationHosoya-Ohmura, S., Mochizuki, N., Suzuki, M., Ohneda, O., Ohneda, K., & Yamamoto, M. P. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605735200 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Gu YZ, Moran SM, Hogenesch JB, et al. Molecu- lar characterization and chromosomal localization of third ␣-class hypoxia inducible factor subunit, HIF-3␣. Gene Expr. 1998;7:205-213.
Cited by
Sorted by citations
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787 · see citing works
Hypoxic regulation of erythropoiesis and iron metabolism
Haase, V. H. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00174.2010 · Cited by 347 · see citing works
Anaemia in kidney disease: harnessing hypoxia responses for therapy
Koury, M. J., & Haase, V. H. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.82 · Cited by 313 · see citing works
The HIF pathway and erythrocytosis
Lee, F. S., & Percy, M. J. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130321 · Cited by 177 · see citing works
- Authors
- Yamashita, T., Ohneda, O., Sakiyama, A., Iwata, F., Ohneda, K., & Fujii-Kuriyama, Y.
- Affiliations
- University of Tsukuba (JP)
- Takasaki University of Health and Welfare (JP)
- Center for TARA, University of Tsukuba, Tsukuba, Japan
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-08-15
- Volume
- 112
- Issue
- 4
- Pages
- 1482-1492
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1984334691
- Cited by
- 44
- References
- 48
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 1 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 4 · 2012: 2
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Science and Technology Agency
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- erythropoiesis, HIF-2α, VCAM-1, endothelial cells, hematopoietic microenvironment, erythropoietin, hypoxia, normocytic anemia, erythroid progenitor cells, oxygen regulation, transcriptional regulation
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Anemia, Animals, Erythropoiesis, Erythropoietin, Gene Expression Regulation, Oxygen, Transcription, Genetic, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Vascular Cell Adhesion Molecule-1, Endothelial Cells, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors
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
