15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression

Venkatesh Kundumani-Sridharan, Jixiao Niu, Dong Wang, Dong Van Quyen, Qiuhua Zhang, Nikhlesh Singh, Jaganathan Subramani, Saradasri Karri, Rao Gadiparthi

Research output: Contribution to journalArticle

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Abstract

To understand the mechanisms underlying 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE]-induced angiogenesis, we studied the role of Egr-1. 15(S)-HETE induced Egr-1 expression in a time-dependent manner in human dermal microvascular endothelial cells (HDMVECs). Blockade of Egr-1 via forced expression of its dominant-negative mutant attenuated 15(S)-HETE-induced HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. 15(S)-HETE-induced Egr-1 expression requires Src activation. In addition, adenovirus-mediated expression of dominantnegative mutant of Src blocked 15(S)-HETE's effects on migration and tube formation of HDMVECs and Matrigel plug angiogenesis. 15(S)-HETE induced fibroblast growth factor-2 (FGF-2) expression rapidly via Src-mediated production of Egr-1. Cloning and mutational analysis of FGF-2 promoter revealed that Egr-1 binding site proximal to transcription start site is required for 15(S)-HETE-induced FGF-2 expression. Neutralizing antibody-mediated suppression of FGF-2 function also attenuated the effects of 15(S)-HETE on HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. Furthermore, in contrast to wild-type mice, 12/15-LOX-/- mice exhibited decreased Matrigel plug angiogenesis in response to AA, which was rescued by 15(S)-HETE. On the basis of these observations, we conclude that 15(S)-HETE-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2. These findings may suggest that 15(S)-HETE could be a potential endogenous regulator of pathologic angiogenesis associated with atherosclerosis and restenosis.

Original languageEnglish (US)
Pages (from-to)2105-2116
Number of pages12
JournalBlood
Volume115
Issue number10
DOIs
StatePublished - Mar 11 2010

Fingerprint

Hydroxyeicosatetraenoic Acids
Fibroblast Growth Factor 2
Endothelial cells
Endothelial Cells
Skin
Cell Movement
Pathologic Neovascularization
Transcription Initiation Site
Cloning
Neutralizing Antibodies
Adenoviridae
Organism Cloning
Atherosclerosis
Binding Sites
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression. / Kundumani-Sridharan, Venkatesh; Niu, Jixiao; Wang, Dong; Van Quyen, Dong; Zhang, Qiuhua; Singh, Nikhlesh; Subramani, Jaganathan; Karri, Saradasri; Gadiparthi, Rao.

In: Blood, Vol. 115, No. 10, 11.03.2010, p. 2105-2116.

Research output: Contribution to journalArticle

Kundumani-Sridharan, Venkatesh ; Niu, Jixiao ; Wang, Dong ; Van Quyen, Dong ; Zhang, Qiuhua ; Singh, Nikhlesh ; Subramani, Jaganathan ; Karri, Saradasri ; Gadiparthi, Rao. / 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression. In: Blood. 2010 ; Vol. 115, No. 10. pp. 2105-2116.
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abstract = "To understand the mechanisms underlying 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE]-induced angiogenesis, we studied the role of Egr-1. 15(S)-HETE induced Egr-1 expression in a time-dependent manner in human dermal microvascular endothelial cells (HDMVECs). Blockade of Egr-1 via forced expression of its dominant-negative mutant attenuated 15(S)-HETE-induced HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. 15(S)-HETE-induced Egr-1 expression requires Src activation. In addition, adenovirus-mediated expression of dominantnegative mutant of Src blocked 15(S)-HETE's effects on migration and tube formation of HDMVECs and Matrigel plug angiogenesis. 15(S)-HETE induced fibroblast growth factor-2 (FGF-2) expression rapidly via Src-mediated production of Egr-1. Cloning and mutational analysis of FGF-2 promoter revealed that Egr-1 binding site proximal to transcription start site is required for 15(S)-HETE-induced FGF-2 expression. Neutralizing antibody-mediated suppression of FGF-2 function also attenuated the effects of 15(S)-HETE on HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. Furthermore, in contrast to wild-type mice, 12/15-LOX-/- mice exhibited decreased Matrigel plug angiogenesis in response to AA, which was rescued by 15(S)-HETE. On the basis of these observations, we conclude that 15(S)-HETE-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2. These findings may suggest that 15(S)-HETE could be a potential endogenous regulator of pathologic angiogenesis associated with atherosclerosis and restenosis.",
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AU - Niu, Jixiao

AU - Wang, Dong

AU - Van Quyen, Dong

AU - Zhang, Qiuhua

AU - Singh, Nikhlesh

AU - Subramani, Jaganathan

AU - Karri, Saradasri

AU - Gadiparthi, Rao

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