p21Cip1 levels differentially regulate turnover of mature endothelial cells, endothelial progenitor cells, and in vivo neovascularization
p21Cip1 levels differentially regulate turnover of mature endothelial cells, endothelial progenitor cells, and in vivo neovascularization
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DOI：
10.1161/01.res.0000119922.71855.56
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发表时间：
2004-03-19
影响因子：
20.1
通讯作者：
Rössig, L
中科院分区：
文献类型：
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作者：
Brühl, T;Heeschen, C;Rössig, L
p21(Cip1) （p21）控制成熟内皮细胞（ECs）的细胞周期进程和凋亡，调节造血祖细胞池的大小和周期。由于循环内皮祖细胞（EPCs）除了促进成熟的内皮祖细胞外，还有助于出生后的新生血管形成，因此我们研究了p21缺陷小鼠中内皮祖细胞和EPCs的调节。纯合子p21（-/-）和杂合子p21（+/-）小鼠的成熟主动脉EC增殖增加，其中p21蛋白水平降低到野生型（WT）的三分之一。相比之下，凋亡敏感性仅在p21（-/-）小鼠中增加了3.5倍，而在p21（+/-）小鼠中没有增加。与此一致的是，p21（-/-）小鼠体内新生血管区域内的内皮细胞凋亡增加，而p21（+/-）小鼠则没有。与WT相比，p21（-/-）小鼠的EPCs数量增加了2倍（P < 0.001）， p21（-/-）小鼠的EPCs克隆扩增能力从25 +/- 4 （WT）增加到57 +/- 8 （P < 0.005）。p21（+/-）小鼠的EPC数量和扩增量同样增加。作为综合终点，反映所有p21影响参数的体内新生血管只在p21（+/-）小鼠中比WT增加（P < 0.001），而在p21（-/-）小鼠中没有增加。总之，缺乏一个p21等位基因的小鼠p21蛋白水平降低与内皮细胞和内皮细胞的增殖增加有关，而内皮细胞在体外和体内对凋亡刺激的存活并未受到损害。在这些条件下，新生血管增加。相比之下，尽管成熟EC和EPC增殖增加，但完全p21缺乏并未导致新生血管的增加。这可能是由于ECs对细胞凋亡的敏化作用。
p21(Cip1) ( p21) controls cell cycle progression and apoptosis in mature endothelial cells ( ECs) and regulates size and cycling of the hematopoietic progenitor cell pool. Because circulating endothelial progenitor cells ( EPCs) contribute to postnatal neovascularization in addition to mature ECs, we investigated the regulation of ECs and EPCs in p21- deficient mice. Mature aortic EC proliferation was increased in homozygous p21(-/-) and heterozygous p21(+/-) mice, in which p21 protein levels are reduced to one third of wild- type ( WT). In contrast, apoptosis sensitivity was increased by 3.5- fold only in p21(-/-), but not in p21(+/-) mice. Consistently, in vivo apoptosis of ECs within areas of neovascularization was elevated in p21(-/-) but not in p21(+/-) mice. EPC numbers were elevated 2- fold in p21(-/-) mice compared with WT ( P < 0.001), and clonal expansion capacity of EPCs was increased from 25 +/- 4 ( WT) to 57 +/- 8 colony- forming units in p21(-/-) mice ( P < 0.005). EPC numbers and expansion were likewise increased in p21(+/-) mice. As the integrative endpoint, in vivo neovascularization reflecting all p21- affected parameters was increased over WT only in p21(+/-) ( P < 0.001), but not in p21(-/-) mice. In conclusion, reduced p21 protein levels of mice lacking one p21 allele are associated with increased proliferation of ECs and EPCs, whereas survival of ECs to apoptotic stimuli in vitro and in vivo is not impaired. Under these conditions, neovascularization was increased. In contrast, complete p21 deficiency did not result in an increased neovascularization despite increased mature EC and EPC proliferation. This may be due to the sensitization of ECs against apoptosis.