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(Stroke. 2009;40:2879.)
© 2009 American Heart Association, Inc.

Research Letters

Nitric Oxide in Vascular Endothelial Growth Factor-Induced Focal Angiogenesis and Matrix Metalloproteinase-9 Activity in the Mouse Brain

Chanhung Z. Lee, MD, PhD; Zheng Xue, MD; Qi Hao, PhD; Guo-Yuan Yang, MD, PhD William L. Young, MD

From the Center for Cerebrovascular Research (C.Z.L., Z.X., Q.H., G.-Y.Y., W.L.Y.), Department of Anesthesia and Perioperative Care, and the Departments of Neurological Surgery (G.-Y.Y., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco, Calif; and the Department of Neurology (Z.X.), Tongji Hospital of Huazhong University of Science and Technology, Wuhan, China.

Correspondence to William L. Young, MD, University of California, San Francisco, Department of Anesthesia and Perioperative Care, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110. E-mail ccr{at}anesthesia.ucsf.edu

Background and Purpose— Vascular endothelial growth factor (VEGF) can induce matrix metalloproteinase (MMP)-9 activities and focal angiogenesis. We hypothesized that VEGF activation of cerebral MMP-9 would require nitric oxide participation.

Methods— We compared the in vivo effects of: (1) N^G-monomethyl-L-arginine, a nonspecific nitric oxide synthase inhibitor; (2) L-N⁶-(1-iminoethyl)lysine, an inducible nitric oxide synthase selective inhibitor; and (3) doxycycline, a known nonspecific inhibitor of MMP in the mouse brain, using in situ zymography and endothelial marker CD31. 3-nitrotyrosine was used as a surrogate for nitric oxide activity. Inflammatory cell markers CD68 and MPO were used to confirm leukocyte infiltration.

Results— VEGF-stimulated MMP-9 activity expressed primarily around cerebral microvessels. N^G-monomethyl-L-arginine suppressed cerebral angiogenesis (P<0.05), especially those microvessels associated with MMP-9 activation (P<0.02) induced by VEGF, comparable to the effect of doxycycline. L-N⁶-(1-iminoethyl)lysine showed similar inhibitory effects. 3-nitrotyrosine confirmed nitric oxide levels in the brain. Compared with the lacZ control, VEGF increased inflammatory cell infiltration, especially macrophages, in the induced brain angiogenic focuses.

Conclusions— Inhibition of nitric oxide production decreased MMP-9 activity and focal angiogenesis in the VEGF-stimulated brain. Both specific and nonspecific inhibition of nitric oxide synthase resulted in similar reductions, suggesting that VEGF-stimulated cerebral MMP activity and angiogenesis are predominantly mediated through inducible nitric oxide synthase, a specific nitric oxide synthase isoform mediating inflammatory responses.

Key Words: matrix metalloproteinase • nitric oxide • vascular endothelial growth factor

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