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Corrigendum Open Access | 10.1172/JCI180863

Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes

Nicolas Skuli, Amar J. Majmundar, Bryan L. Krock, Rickson C. Mesquita, Lijoy K. Mathew, Zachary L. Quinn, Anja Runge, Liping Liu, Meeri N. Kim, Jiaming Liang, Steven Schenkel, Arjun G. Yodh, Brian Keith, and M. Celeste Simon

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Published April 15, 2024 - More info

Published in Volume 134, Issue 8 on April 15, 2024
J Clin Invest. 2024;134(8):e180863. https://doi.org/10.1172/JCI180863.
© 2024 Skuli et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 15, 2024 - Version history
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Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes
Nicolas Skuli, … , Brian Keith, M. Celeste Simon
Nicolas Skuli, … , Brian Keith, M. Celeste Simon
Research Article Vascular biology Article has an altmetric score of 9

Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes

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Abstract

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.

Authors

Nicolas Skuli, Amar J. Majmundar, Bryan L. Krock, Rickson C. Mesquita, Lijoy K. Mathew, Zachary L. Quinn, Anja Runge, Liping Liu, Meeri N. Kim, Jiaming Liang, Steven Schenkel, Arjun G. Yodh, Brian Keith, M. Celeste Simon

×

Original citation: J Clin Invest. 2012;122(4):1427–1443. https://doi.org/10.1172/JCI57322

Citation for this corrigendum: J Clin Invest. 2024;134(8):e180863. https://doi.org/10.1172/JCI180863

The authors recently became aware that the image presented in Figure 4A for the 21% O2 KO H2.1 sample was a different crop as the image presented in Figure 4A for the 21% O2 Ctrl H2.1 sample. In addition, the image presented in Figure 4A for the 0.5% O2 KO H2.1. sample was a duplicate of the image presented in Figure 6E for the Ctrl H2.1/0.5% O2/DMSO sample. The authors were able to provide the correct images from the original experiment and replaced the 21% O2 KO H2.1 and 0.5% O2 KO H2.1 in Figure 4A. The correct figure panel is shown below. These corrections do not alter any conclusions of the paper.

In addition, the authors wish to clarify that the images presented in Figure 8A are shown again in Supplemental Figure 10A as part of the full time course of the experiment (day 14 column). The updated legend text for Supplemental Figure 10A appears below:

Supplemental Figure 10. Dll4 and Dll4/Ang2 are sufficient to reverse endothelial HIF-2α deletion phenotypes in a hindlimb ischemia model. Blood flow, foot movement score and necrosis were assessed for Ctrl and KO mice after femoral artery ligation and intramuscular injection of an empty viral vector, a viral vector expressing Dll4 or Dll4 vector in combination with intravenous Ang2. Blood flow was quantified by laser Doppler. (A–B) Representative images (A) obtained by laser Doppler showing the efficiency of the surgery distally to the occlusion side and the progressive blood flow recovery after 21 days for Ctrl and KO mice. Note that images in the day 14 column also appear in Figure 8A. (B) Quantitative laser Doppler analysis showing the left-to-right limb ratio after occlusion of the femoral artery at day 7. KO mice display a delayed restoration in perfusion compared to Ctrl mice. However, flow is completely restored for mice injected with a viral vector expressing Dll4 or Dll4 vector in combination with Ang2. (C) Foot movement was determined and scored between 0 and 4 as a functional read out parameter to assess flow deficits after ischemia. Active foot movement was significantly impaired in KO mice and restored in the presence of Dll4 vector or Dll4 vector in combination with Ang2. (D) Percentage of mice in each group presenting necrosis or amputation was determined. More KO mice had to be euthanized due to amputation or necrosis of the limb. Injection of Dll4 vector or Dll4 vector in combination with Ang2 significantly decreases necrosis and amputation. (Ctrl n = 20, KO n = 20) Data are means ± SEM. *P < 0.05 and **P < 0.01.

The authors regret the errors.

Footnotes

See the related article at Endothelial Hypoxia Inducible Factor-2alpha (HIF-2α) regulates murine pathological angiogenesis and revascularization processes.

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