Angiostatin: A negative regulator of endothelial-dependent vasodilation

• Published in: Circulation (New York, N.Y.) N.Y.), 2003-02, Vol.107 (6), p.803-806
• Main Authors: KOSHIDA, Ryoji, JINGSONG OU, MATSUNAGA, Toshiro, CHILIAN, William M, OLDHAM, Keith T, ACKERMAN, Allan W, PRITCHARD, Kirkwood A
• Format: Article
• Language: English
• Subjects: Angiostatins; Animals; Arterioles - drug effects; Arterioles - physiology; Biological and medical sciences; Blood vessels and receptors; Blotting, Western; Cattle; Cells, Cultured; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; HSP90 Heat-Shock Proteins - metabolism; In Vitro Techniques; Male; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type III; Peptide Fragments - pharmacology; Plasminogen - pharmacology; Precipitin Tests; Protein Binding - drug effects; Protein Binding - physiology; Rats; Rats, Sprague-Dawley; Superoxides - metabolism; Vasodilation - drug effects; Vasodilation - physiology; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000057551.88851.09

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-. 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. 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.