1. Mol Cancer Res. 2009 Jul;7(7):1056-63. Epub 2009 Jun 30.

Vascular caveolin deficiency supports the angiogenic effects of nitrite, a major 
end product of nitric oxide metabolism in tumors.

Frérart F, Lobysheva I, Gallez B, Dessy C, Feron O.

Unit of Pharmacology and Therapeutics, Université Catholique de Louvain, UCL-FATH
5349, Brussels, Belgium.

The biological status of nitrite recently evolved from an inactive end product of
nitric oxide (NO) metabolism to a major intravascular and tissue storage of NO.
Several enzymes and proteins may indeed work as nitrite reductases. The
endothelial NO synthase (eNOS) is proposed to be one of them, particularly when
oxygen is lacking. Here, we examined whether the lack of caveolin, a scaffold
protein known to limit eNOS activity under basal conditions and to be
down-regulated in tumor vessels, could favor the reconversion of nitrite into NO 
and thereby promote angiogenesis. We found that nitrite-rich serum from
caveolin-deficient mice and exogenous nitrite exert proangiogenic effects on
aortic explants cultured in a three-dimensional collagen matrix. We identified a 
higher intrinsic capacity of caveolin-deficient vessels and endothelial cells to 
convert nitrite into bioactive NO. These effects did occur under moderate hypoxia
and were abolished on exposure to a NO scavenger. Evidence for eNOS acting as a
nitrite reductase derived from the failure to reproduce the proangiogenic effects
of nitrite on eNOS-deficient aorta rings and endothelial cells. Finally, in a
mouse tumor model, we documented the higher nitrite content in hypoxic tumors and
identified inducible NO synthase as the major source of nitrite. Altogether,
these data identify the lack of caveolin observed in the tumor vasculature as a
favorable ground for nitrite-driven formation of endothelial tubes in the hypoxic
tumor microenvironment. This work also strengthens the therapeutic value of the
modulation of caveolin expression to interfere with tumor angiogenesis.

PMID: 19567781 [PubMed - in process]