Published online before print February 10, 2003, doi: 10.1161/01.CIR.0000057551.88851.09
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(Circulation. 2003;107:803.)
© 2003 American Heart Association, Inc.
Brief Rapid Communications |
Angiostatin
A Negative Regulator of Endothelial-Dependent Vasodilation
From the Departments of Physiology (R.K., T.M., W.M.C.), Pediatric Surgery (J.O., K.T.O., A.W.A., K.A.P.), and Pharmacology & Toxicology (K.A.P.); Cardiovascular Center (R.K., J.O., T.M., W.M.C., K.T.O., K.A.P.); and Free Radical Research Center (K.A.P.), Medical College of Wisconsin, Milwaukee. Dr Chilian is now Chairman of Physiology at Louisiana State University.
Correspondence to Kirkwood A. Pritchard, Jr, PhD, Medical College of Wisconsin, 8701 Watertown Plank Rd, CVC M4060, Milwaukee, WI 53226 (E-mail kpritch{at}mcw.edu), or William M. Chilian, PhD, Professor and Head, Department of Physiology, Louisiana State University Health Science Center, 1901 Perido St, New Orleans, LA 70112 (E-mail chilian@LSUHSC.edu).
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 (
). This avenue of investigation was based on recent reports suggesting that hsp90 modulates NOS production of ·NO and .
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 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 generation in stimulated BAECs by an L
-nitroargininemethylester (L-NAME)–inhibitable mechanism.
Conclusions— These data indicate angiostatin alters endothelial function by allowing eNOS to generate on activation. Such changes in enzyme function begin to explain, in part, why angiostatin is antiangiogenic and impairs endothelium-dependent vasodilation.
Key Words: angiostatin • nitric oxide synthase, endothelial • heat-shock protein 90 • nitric oxide • superoxides
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