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Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung.

by Bhandari V, Choo-Wing R, Chapoval SP, Lee CG, Tang C, Kim YK, Ma B, Baluk P, Lin MI, McDonald DM, Homer RJ, Sessa WC, Elias JA
Proceedings of the National Academy of Sciences of the United States of America.

Article Abstract:

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.

questionable relevance to asthma

By: Anonymous - Wed 3/28/2007 AM

The potential role of NO in VEFG-induced changes in inflammation and systemic angiogenesis is clearly important and nicely documented in this study. However, for two reasons, there is serious concern over the attempt to link these results to asthma. The first relates to the fact that the vascular changes observed were shown for the systemic circulation to the trachea. However, in the mouse there is no functional systemic circulation below the mainstem bronchi, so any vascular changes or fluid leakage could have no impact at all on the size of the airways in the lung. Related to these potential changes in airflow into the lung is perhaps an even more serious concern. The authors unfortunately used Penh as the critical functional link to the airways in vivo. It is now well documented that Penh has no theoretical link at all to the size of the airways, which is the requisite measurement needed to be able to relate to the pathologic airway narrowing in asthma. This inappropriateness has been supported in a publication by international group of leading respiratory scientists and clinicians. It is thus doubly regrettable that not only did the authors choose this inappropriate measurement, but also that the reviewers of the paper allowed it to be promulgated in this otherwise very prestigious journal. As it stands now, the paper elegantly shows a potentially important role for this VEGF - NO interaction in the pattern of breathing (which is what Penh actually measures). While this may be important in the control of ventilation or other lung diseases, until proper in vivo measurements of airway smooth muscle responsiveness are made, it would seem quite improper to relate the work to asthma.

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