Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung.
VEGF, nitric oxide (NO), inflammation, and vascular- and extravascular remodeling coexist in asthma and other disorders. In these responses, VEGF regulates angiogenesis. VEGF also induces inflammation and remodeling. The mechanisms of the latter responses have not been defined, however. We hypothesized that VEGF-induces extravascular tissue responses via NO-dependent mechanisms. To evaluate this hypothesis, we compared the effects of transgenic VEGF165 in lungs from normal mice, mice treated with pan-NO synthase (NOS) or endothelial NOS (eNOS) inhibitors, and mice with null mutations of inducible NOS (iNOS) or eNOS. These studies demonstrate that VEGF selectively stimulates eNOS and iNOS. They also demonstrate that VEGF induces pulmonary alterations via NO-dependent and -independent mechanisms with angiogenesis, edema, mucus metaplasia, airway hyperresponsiveness, lymphocyte accumulation, dendritic cell hyperplasia and S-nitrosoglutathione reductase stimulation being NO-dependent and dendritic cell activation being NO-independent. Furthermore, they demonstrate that eNOS and iNOS both contribute to these responses. NO/NOS-based interventions may be therapeutic in VEGF-driven inflammation and remodeling.
Bhandari
Vineet
V
Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, LCI 401-B, New Haven, CT 06520-8057, USA.
Choo-Wing
Rayman
R
Chapoval
Svetlana P
SP
Lee
Chun G
CG
Tang
C
C
Kim
Y K
YK
Ma
Bing
B
Baluk
Peter
P
Lin
Michelle I
MI
McDonald
Donald M
DM
Homer
Robert J
RJ
Sessa
William C
WC
Elias
Jack A
JA
D000426:Alcohol Dehydrogenase; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D005088:Exocrine Glands / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D019001:Nitric Oxide Synthase; D005980:Glutathione Reductase