Eintrag weiter verarbeiten
15(S)-hydroxyeicosatetraenoic acid–induced angiogenesis requires Src-mediated Egr-1–dependent rapid induction of FGF-2 expression
Gespeichert in:
| Zeitschriftentitel: | Blood |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | Blood, 115, 2010, 10, S. 2105-2116 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Hematology
|
| Schlagwörter: |
| Zusammenfassung: | <jats:title>Abstract</jats:title><jats:p>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 dominant-negative 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.</jats:p> |
|---|---|
| Umfang: | 2105-2116 |
| ISSN: |
0006-4971
1528-0020 |
| DOI: | 10.1182/blood-2009-09-241802 |