Improved vascular survival and growth in the mouse model of hindlimb ischemia by a remote signaling mechanism.
Improved vascular survival and growth in the mouse model of hindlimb ischemia by a remote signaling mechanism.
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DOI：
10.1016/j.ajpath.2013.11.032
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发表时间：
2014-03
期刊：
影响因子：
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通讯作者：
K. Takeda;L. Duan;Hiromi Takeda;G. Fong
中科院分区：
文献类型：
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作者：
K. Takeda;L. Duan;Hiromi Takeda;G. Fong
脯氨酰羟化酶结构域蛋白（PHD）的缺乏可能导致缺氧诱导因子-α蛋白的积累，后者通过旁分泌机制激活局部血管生成反应。在这里，我们调查是否角质形成细胞特异性PHD缺陷可能促进血管的存活和生长在一个遥远的缺血组织通过远程信号机制。我们产生了携带角质细胞特异性Phd 2敲除（kPhd 2KO）的小鼠，并进行股动脉结扎。相对于野生型对照，kPhd 2KO小鼠显示改善的缺血后肢血管存活和动脉生成，导致后肢灌注的加速恢复和上级肌肉再生。在1型和2型糖尿病小鼠中也观察到类似的保护作用。在分子水平上，kPhd 2KO小鼠表皮组织中缺氧诱导因子-1 α蛋白的丰度和血管内皮生长因子-A的表达均增加，并伴随着血管内皮生长因子-A血浆浓度的增加。与在所有皮肤组织中PHD 2缺陷的kPhd 2KO小鼠相反，后肢皮肤组织中的局部kPhd 2KO没有类似的作用，排除旁分泌信号传导作为主要机制。证实了远端效应的存在，肝细胞特异性Phd 2基因敲除也保护了后肢免受缺血损伤。这些数据表明，缺血损伤组织中的血管存活和生长可以通过抑制远端组织中的PHD 2来刺激，并且可以提供高效的血管生成疗法，而无需直接进入靶组织。
Deficiencies in prolyl hydroxylase domain proteins (PHDs) may lead to the accumulation of hypoxia-inducible factor-α proteins, the latter of which activate local angiogenic responses by paracrine mechanisms. Here, we investigate whether a keratinocyte-specific PHD deficiency may promote vascular survival and growth in a distantly located ischemic tissue by a remote signaling mechanism. We generated mice that carry a keratinocyte-specificPhd2knockout (kPhd2KO) and performed femoral artery ligation. Relative to wild-type controls, kPhd2KO mice displayed improved vascular survival and arteriogenesis in ischemic hind limbs, leading to the accelerated recovery of hindlimb perfusion and superior muscle regeneration. Similar protective effects were also seen in type 1 and type 2 diabetic mice. Molecularly, both abundance of hypoxia-inducible factor-1α protein and expression of vascular endothelial growth factor-A were increased in epidermal tissues of kPhd2KO mice, accompanied by increased plasma concentration of vascular endothelial growth factor-A. Contrary to kPhd2KO mice, which are PHD2 deficient in all skin tissues, localized kPhd2KO in hindlimb skin tissues did not have similar effects, excluding paracrine signaling as a major mechanism. Confirming the existence of remote effects, hepatocyte-specificPhd2knockout also protected hind limbs from ischemia injury. These data indicate that vascular survival and growth in ischemia-injured tissue may be stimulated by suppressing PHD2 in a remotely located tissue and may provide highly effective angiogenesis therapies without the need for directly accessing target tissues.