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首页> 外文期刊>Molecular cancer research: MCR >Vascular caveolin deficiency supports the angiogenic effects of nitrite, a major end product of nitric oxide metabolism in tumors.
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Vascular caveolin deficiency supports the angiogenic effects of nitrite, a major end product of nitric oxide metabolism in tumors.

机译：血管空洞蛋白缺乏症支持亚硝酸盐（一氧化氮在肿瘤中代谢的主要终产物）的血管生成作用。

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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.
机译：亚硝酸盐的生物学状态最近从一氧化氮（NO）代谢的无活性最终产物演变为主要的血管内和组织NO储存。几种酶和蛋白质确实可以充当亚硝酸盐还原酶。内皮一氧化氮合酶（eNOS）是其中之一，特别是在缺氧的情况下。在这里，我们检查了caveolin是否缺乏，一种已知在基础条件下限制eNOS活性并在肿瘤血管中下调的支架蛋白，是否有助于亚硝酸盐重新转化为NO，从而促进血管生成。我们发现，来自空洞蛋白缺陷小鼠的富含亚硝酸盐的血清和外源亚硝酸盐对在三维胶原蛋白基质中培养的主动脉外植体产生促血管生成作用。我们鉴定出了较高的内在能力，即缺乏穴蛋白的血管和内皮细胞将亚硝酸盐转化为具有生物活性的NO。这些影响确实在中度低氧下发生，并且在暴露于NO清除剂后被消除。 eNOS充当亚硝酸盐还原酶的证据源自未能重现亚硝酸盐对eNOS缺乏主动脉环和内皮细胞的促血管生成作用。最后，在小鼠肿瘤模型中，我们记录了低氧肿瘤中较高的亚硝酸盐含量，并确定了诱导型一氧化氮合酶是亚硝酸盐的主要来源。总而言之，这些数据表明在缺氧的肿瘤微环境中，在肿瘤脉管系统中观察到的空洞蛋白缺乏是亚硝酸盐驱动的内皮管形成的有利基础。这项工作还加强了小窝蛋白表达的调节，以干扰肿瘤血管生成的治疗价值。

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