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Angiostatin: a negative regulator of endothelial-dependent vasodilation. Circulation 2003 Feb 18;107(6):803-6

Date

02/20/2003

Pubmed ID

12591747

DOI

10.1161/01.cir.0000057551.88851.09

Scopus ID

2-s2.0-0037448787   50 Citations

Abstract

BACKGROUND: Angiostatin is known to inhibit certain aspects of endothelial function, eg, angiogenesis. Here we investigated the effects of angiostatin on another aspect of endothelial function, vasodilation, and examined mechanisms of inhibition--namely, association of heat-shock protein 90 (hsp90) with endothelial nitric oxide synthase (eNOS) and endothelial generation of nitric oxide (*NO) and superoxide anion (O2-). This avenue of investigation was based on recent reports suggesting that hsp90 modulates NOS production of *NO and O2-.

METHODS AND RESULTS: Effects of angiostatin on vasodilation were determined in arterioles with the use of videomicroscopy in response to endothelium- and *NO-dependent vasodilators, acetylcholine (ACh) and vascular endothelial growth factor (VEGF), and an endothelium-independent agonist, papaverine. Association of hsp90 with eNOS was determined in rat aortas and bovine aortic endothelial cells (BAECs). Effects of angiostatin on *NO and O2- generation by BAECs were determined by ozone chemiluminescence and superoxide dismutase (SOD)--inhibitable ferricytochrome c reduction, respectively. Angiostatin impaired vasodilation mediated by ACh and VEGF but not papaverine. Pretreating arterioles with polyethylene glycolated--SOD (PEG-SOD) improved vasodilation to ACh and VEGF. Angiostatin decreased the association of hsp90 with eNOS in aortas and BAEC cultures and increased O2- generation in stimulated BAECs by an Lgamma-nitroargininemethylester (L-NAME)--inhibitable mechanism.

CONCLUSIONS: These data indicate angiostatin alters endothelial function by allowing eNOS to generate O2- on activation. Such changes in enzyme function begin to explain, in part, why angiostatin is antiangiogenic and impairs endothelium-dependent vasodilation.

Author List

Koshida R, Ou J, Matsunaga T, Chilian WM, Oldham KT, Ackerman AW, Pritchard KA Jr

Authors

Keith T. Oldham MD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiostatins
Animals
Arterioles
Blotting, Western
Cattle
Cells, Cultured
Endothelium, Vascular
Enzyme Inhibitors
HSP90 Heat-Shock Proteins
In Vitro Techniques
Male
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Peptide Fragments
Plasminogen
Precipitin Tests
Protein Binding
Rats
Rats, Sprague-Dawley
Superoxides
Vasodilation
Vasodilator Agents
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a