Hypoxia Increases Nitric Oxide-Dependent Inhibition of Angiogenic Growth
Arce, Cristina (Universitat de València. Departament de Farmacologia)
Vicente, Diana (Universitat de València. Departament de Farmacologia)
Monto, Fermí (Universitat de València. Departament de Farmacologia)
González, Laura (Universitat de València. Departament de Farmacologia)
Nuñez, Cristina (Universitat de València. Departament de Farmacologia)
Victor, Victor Manuel (Hospital Universitari Doctor Peset (València))
Jiménez Altayó, Francesc (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
D'Ocon, Pilar (Universitat de València. Departament de Farmacologia)

Date:	2021
Abstract:	Nitric oxide (NO) is a proangiogenic factor acting through the soluble guanylate cyclase (sGC) pathway. However, angiogenic growth increases energy demand, which may be hampered by NO inhibition of cytochrome c oxidase (CcO). Then, NO activity would be the balanced result of sGC activation (pro-angiogenic) and CcO inhibition (anti-angiogenic). NO activity in a rat and eNOS mice aortic ring angiogenic model and in a tube formation assay (human aortic endothelial cells) were analyzed in parallel with mitochondrial O consumption. Studies were performed with NO donor (DETA-NO), sGC inhibitor (ODQ), and NOS or nNOS inhibitors (L-NAME or SMTC, respectively). Experiments were performed under different O concentrations (0-21%). Key findings were: (i) eNOS-derived NO inhibits angiogenic growth by a mechanism independent on sGC pathway and related to inhibition of mitochondrial O consumption; (ii) NO inhibition of the angiogenic growth is more evident in hypoxic vessels; (iii) in the absence of eNOS-derived NO, the modulation of angiogenic growth, related to hypoxia, disappears. Therefore, NO, but not lower O levels, decreases the angiogenic response in hypoxia through competitive inhibition of CcO. This anti-angiogenic activity could be a promising target to impair pathological angiogenesis in hypoxic conditions, as it occurs in tumors or ischemic diseases.
Grants:	Ministerio de Economía y Competitividad SAF2013-45362-R Instituto de Salud Carlos III PI19/00838
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Nitric oxide ; Hypoxia ; Angiogenesis ; Mitochondrial O2 consumption
Published in:	International journal of translational medicine, Vol. 1, Núm. 3 (december 2021) , p. 366-380, ISSN 2673-8937

DOI: 10.3390/ijtm1030022

15 p, 2.9 MB

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