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Matrix Biol. 2018 Jan;65:45-58. doi: 10.1016/j.matbio.2017.07.002. Epub 2017 Aug 5.

HIF-1α represses the expression of the angiogenesis inhibitor thrombospondin-2.

Author information

1
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: smaclauc@bu.edu.
2
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: Nicole.Calabro@yale.edu.
3
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Cardiovascular Medicine, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: Yan.Huang@yale.edu.
4
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: mkrishna@college.harvard.edu.
5
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: tbancrof@fredhutch.org.
6
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: Tanuj.Sharma@yale.edu.
7
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Cardiovascular Medicine, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: Jun.Yu@temple.edu.
8
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pharmacology, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: William.sessa@yale.edu.
9
Section of Cardiovascular Medicine, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: Frank.Giordano@yale.edu.
10
Interdepartmental Program in Vascular Biology and Therapeutics, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Amistad Building, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: Themis.Kyriakides@yale.edu.

Abstract

Thrombospondin-2 (TSP2) is a potent inhibitor of angiogenesis whose expression is dynamically regulated following injury. In the present study, it is shown that HIF-1α represses TSP2 transcription. Specifically, in vitro studies demonstrate that the prolyl hydroxylase inhibitor DMOG or hypoxia decrease TSP2 expression in fibroblasts. This effect is shown to be via a transcriptional mechanism as hypoxia does not alter TSP2 mRNA stability and this effect requires the TSP2 promoter. In addition, the documented repressive effect of nitric oxide (NO) on TSP2 is shown to be non-canonical and involves stabilization of hypoxia inducible factor-1a (HIF-1α). The regulation of TSP2 by hypoxia is supported by the in vivo observation that TSP2 has spatiotemporal expression distinct from regions of hypoxia in gastrocnemius muscle following murine hindlimb ischemia (HLI). A role for TSP2 regulation by HIF-1α is supported by the dysregulation of TSP2 expression in SM22α-cre HIF-1α KO mice following HLI. Indeed, there is a reduction in blood flow recovery in the SM22a-cre HIF-1α KO mice compared to littermate controls following HLI surgery, associated with impaired recovery and increased TSP2 levels. Moreover, SM22α-cre HIF-1α KO smooth muscle cells mice have increased TSP2 mRNA levels that persist in hypoxia. These findings identify a novel, ischemia-induced pro-angiogenic mechanism involving the transcriptional repression of TSP2 by HIF-1α.

KEYWORDS:

Angiogenesis; Hypoxia; Hypoxia-inducible factor (HIF); Thrombospondin; Transcription

PMID:
28789925
PMCID:
PMC5973794
DOI:
10.1016/j.matbio.2017.07.002
[Indexed for MEDLINE]
Free PMC Article

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