Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice
Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice
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DOI：
10.1172/jci1293
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发表时间：
1998-03-15
影响因子：
15.9
通讯作者：
Huang, PL
中科院分区：
文献类型：
--
作者：
Moroi, M;Zhang, L;Huang, PL
为了将动脉粥样硬化作为一种受基因组成和环境影响的复杂遗传疾病进行解剖，我们(a)建立了一个可重复的新生内膜生长小鼠模型；(b)评估了单个基因（内皮型一氧化氮合酶）被破坏的影响，该基因被认为是内膜生长的核心，(c)检查了性别和妊娠对血管反应的修饰作用，在股动脉周围放置袖带可引起可复制的内膜生长。我们通过定量形态学测量来评估对损伤的反应，测量内膜与内侧（I/M）体积比。在野生型小鼠中，袖带放置引起明显的内膜增殖而不影响介质，导致I/M比率为31% （SV129雄性）和27% （C57BL/6雄性）。eNOS突变雄性小鼠的内膜生长程度要大得多（I/M比为70%）。雌性小鼠比雄性小鼠表现出更少的内膜反应，尽管eNOS突变雌性小鼠仍然比野生型雌性小鼠有更多的内膜反应。然而，最引人注目的是怀孕的影响，它从根本上消除了内膜对损伤的反应，甚至超过了eNOS突变的影响。我们的结论是，eNOS缺陷是一种内膜增殖的遗传易感性，这种易感性在男性中增强，并且可能被怀孕所覆盖。
To begin to dissect atherogenesis as a complex genetic disorder affected by genetic makeup and environment, we have (a) generated a reproducible mouse model of neointimal growth; (b) evaluated the effect of disruption of a single gene, endothelial nitric oxide synthase, believed to be central to intimal growth, and (c) examined the modifying effects of gender and pregnancy upon the vascular response, Cuff placement around the femoral artery causes reproducible intimal growth. We assessed the response to injury by quantitative morphometry, measuring the intimal to medial (I/M) volume ratio. In wild-type mice, cuff placement causes pronounced intimal proliferation without affecting the media, resulting in I/M ratios of 31% (SV129 males) and 27% (C57BL/6 males). eNOS mutant male mice have a much greater degree of intimal growth (I/M ratio of 70%). Female mice show less intimal response than do males, although eNOS mutant female mice still have more response than do wild-type females. Most dramatic, however, is the effect of pregnancy, which essentially abolishes the intimal response to injury, even overriding the effect of eNOS mutation. We conclude that eNOS deficiency is a genetic predisposition to intimal proliferation that is enhanced by male gender, and that may be overridden by pregnancy.