Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells
Endothelial cell-derived semaphorin 3A inhibits filopodia formation by blood vascular tip cells
复制标题
DOI：
10.1242/dev.127670
复制
发表时间：
2016-02-15
期刊：
影响因子：
4.6
通讯作者：
Detmar, Michael
中科院分区：
文献类型：
--
作者：
Ochsenbein, Alexandra M.;Karaman, Sinem;Detmar, Michael
血管内皮生长因子（VEGF）-A是众所周知的血管生成的主要化学引诱物驱动剂-从预先存在的血管形成新的血管。然而，微调这种血管生成过程的驱避因子仍然缺乏特征。我们使用遗传小鼠模型研究了内皮细胞源性脑信号蛋白3A（Sema 3A）在视网膜血管生成中的表达和功能作用。我们发现Sema 3a mRNA表达在神经节细胞层和Sema 3A蛋白存在于较大的血管和新生儿视网膜血管的生长前沿。视网膜血管表达Sema 3A受体neuropilin-1和plexin-A1。为了研究Sema 3A的内皮细胞特异性作用，我们通过组成型或诱导型血管内皮钙粘蛋白-Cre介导的基因破坏产生内皮细胞特异性Sema 3A敲除小鼠品系。我们发现，在这些小鼠的新生视网膜中，尖端细胞丝状伪足的数量和长度均显著增加，并且前缘生长模式不规则。视网膜外植体实验表明，重组Sema 3A显着减少VEGF-A诱导的丝状伪足的形成。内皮细胞特异性敲除Sema 3A对成年小鼠的血管密度或皮肤血管渗漏没有影响。这些发现表明，内皮细胞衍生的Sema 3A对VEGF-A诱导的尖端细胞丝状伪足发挥排斥功能，并且缺乏这种信号传导不能被Sema 3A的旁分泌来源所拯救。
Vascular endothelial growth factor (VEGF)-A is a well-known major chemoattractant driver of angiogenesis - the formation of new blood vessels from pre-existing ones. However, the repellent factors that fine-tune this angiogenic process remain poorly characterized. We investigated the expression and functional role of endothelial cell-derived semaphorin 3A (Sema3A) in retinal angiogenesis, using genetic mouse models. We found Sema3a mRNA expression in the ganglion cell layer and the presence of Sema3A protein on larger blood vessels and at the growing front of blood vessels in neonatal retinas. The Sema3A receptors neuropilin-1 and plexin-A1 were expressed by retinal blood vessels. To study the endothelial cell-specific role of Sema3A, we generated endothelial cell-specific Sema3A knockout mouse strains by constitutive or inducible vascular endothelial cadherin-Cre-mediated gene disruption. We found that in neonatal retinas of these mice, both the number and the length of tip cell filopodia were significantly increased and the leading edge growth pattern was irregular. Retinal explant experiments showed that recombinant Sema3A significantly decreased VEGF-A-induced filopodia formation. Endothelial cell-specific knockout of Sema3A had no impact on blood vessel density or skin vascular leakage in adult mice. These findings indicate that endothelial cell-derived Sema3A exerts repelling functions on VEGF-A-induced tip cell filopodia and that a lack of this signaling cannot be rescued by paracrine sources of Sema3A.