The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes
Open accessAbstract
Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2α expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2α-deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2α-dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2α-dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2α in ECs. These results indicate that HIF-1α and HIF-2α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.
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Cites
Hypoxia-inducible factors and the response to hypoxic stress
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HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
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Self-citationThe impact of O2 availability on human cancer
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Hypoxia requires Notch signaling to maintain the undifferentiated cell state
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Self-citationAcute postnatal ablation of Hif-2 α results in anemia
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Targeting hypoxia cell signaling for cancer therapy
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Cited by
The hypoxic tumour microenvironment
Petrova, V., Annicchiarico-Petruzzelli, M., Melino, G., & Amelio, I. (2018) · Oncogenesis · doi:10.1038/s41389-017-0011-9 · Cited by 1,019
Emami Nejad, A., Najafgholian, S., Rostami, A., Sistani, A., Shojaeifar, S., Esparvarinha, M., Nedaeinia, R., Haghjooy Javanmard, S., Taherian, M., Ahmadlou, M., et al. (2021) · Cancer Cell International · doi:10.1186/s12935-020-01719-5 · Cited by 693
Villa, E., Critelli, R., Lei, B., Marzocchi, G., Cammà, C., Giannelli, G., Pontisso, P., Cabibbo, G., Enea, M., Colopi, S., et al. (2016) · Gut · doi:10.1136/gutjnl-2014-308483 · Cited by 262
Postischemic Revascularization: From Cellular and Molecular Mechanisms to Clinical Applications
Silvestre, J.-S., Smadja, D. M., & Lévy, B. I. (2013) · Physiological Reviews · doi:10.1152/physrev.00006.2013 · Cited by 255
Hypoxia-inducible factor signaling in pulmonary hypertension
Pullamsetti, S. S., Mamazhakypov, A., Weissmann, N., Seeger, W., & Savai, R. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137558 · Cited by 234
Metadata
- Authors
- Skuli, N., Majmundar, A. J., Krock, B. L., Mesquita, R. C., Mathew, L. K., Quinn, Z. L., Runge, A., Liu, L., Kim, M. N., Liang, J., Schenkel, S., Yodh, A. G., Keith, B., & Simon, M. C.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-04-02
- Volume
- 122
- Issue
- 4
- Pages
- 1427-1443
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2114719275
- Cited by
- 200
- References
- 13
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- green
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- Skuli, N., Majmundar, A. J., Krock, B. L., Mesquita, R. C., Mathew, L. K., Quinn, Z. L., Runge, A., Liu, L., Kim, M. N., Liang, J., Schenkel, S., Yodh, A. G., Keith, B., & Simon, M. C. (2012). Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes. Journal of Clinical Investigation. https://doi.org/10.1172/jci57322
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