Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.
Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.
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DOI：
10.1161/circresaha.111.249847
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发表时间：
2012-01-06
影响因子：
20.1
通讯作者：
Cleaver O
中科院分区：
文献类型：
--
作者：
Meadows SM;Fletcher PJ;Moran C;Xu K;Neufeld G;Chauvet S;Mann F;Krieg PA;Cleaver O
阳性信号，如血管内皮因子（VEGF），在血管形成过程中将内皮细胞（EC）引导至特定位置。关于排斥信号对血管成形的贡献知之甚少。最近，“神经元引导线索”（NGC）已被证明影响EC的行为，特别是在指导萌芽血管生成排斥EC。然而，它们在新生血管形成过程中的作用仍然未被探索。识别引导和形成第一批哺乳动物血管的信号。使用遗传小鼠模型，我们表明，血管雕刻通过生成刻板的无血管区EC排斥线索。我们证明，Semaphorin 3E（Sema 3E）是一个关键因素，形状配对的DA在小鼠中，作为sema 3E-/-胚胎发育异常分支的主动脉丛与一个显着狭窄的无血管中线。在体外培养和禽类移植实验中显示出强烈的排斥的EC的Sema 3E表达细胞。我们进一步确定小鼠脊索作为一个丰富的来源，多个冗余的NGC。缺乏脊索的小鼠胚胎由于无血管中线的缺失而不能形成紧密的主动脉血管，但仍保持着外侧无血管区。我们证明，侧无血管区直接产生的侧板中胚层（LPM），Sema 3E的一个重要来源。这些发现表明，Sema 3E产生的无血管区是哺乳动物心血管模式的关键调节因子，并且是第一个确定LPM的排斥作用的区域。整合来自各种组织的多个（在某些情况下是冗余的）排斥性线索对于形成第一个胚胎血管至关重要。
Positive signals, such as vascular endothelial factor (VEGF), direct endothelial cells (ECs) to specific locations during blood vessel formation. Less is known about repulsive signal contribution to shaping vessels. Recently, ’neuronal guidance cues’ (NGCs) have been shown to influence EC behavior, particularly in directing sprouting angiogenesis by repelling ECs. However, their role during de novo blood vessel formation remains unexplored. To identify signals that guide and pattern the first mammalian blood vessels. Using genetic mouse models, we show that blood vessels are sculpted via the generation of stereotyped avascular zones by EC-repulsive cues. We demonstrate that Semaphorin3E (Sema3E) is a key factor that shapes the paired DA in mouse, as sema3E-/- embryos develop an abnormally branched aortic plexus with a markedly narrowed avascular midline. In vitro cultures and avian grafting experiments show strong repulsion of ECs by Sema3E-expressing cells. We further identify the mouse notochord as a rich source of multiple redundant NGCs. Mouse embryos that lack notochords fail to form cohesive aortic vessels due to loss of the avascular midline, yet maintain lateral avascular zones. We demonstrate that lateral avascular zones are directly generated by the lateral plate mesoderm (LPM), a critical source of Sema3E. These findings demonstrate that Sema3E-generated avascular zones are critical regulators of mammalian cardiovascular patterning, and are the first to identify a repulsive role for the LPM. Integration of multiple, and in some cases redundant, repulsive cues from various tissues is critical to patterning the first embryonic blood vessels.