Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis?
Intussusceptive-like angiogenesis in human fetal lung xenografts: Link with bronchopulmonary dysplasia-associated microvascular dysangiogenesis?
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DOI：
10.3109/01902148.2015.1080321
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发表时间：
2015-10-21
影响因子：
1.7
通讯作者：
Boekelheide, Kim
中科院分区：
文献类型：
--
作者：
De Paepe, Monique E.;Chu, Sharon;Boekelheide, Kim
工作背景：人胎肺异种移植物显示出一种不寻常的非发芽，丛形成血管生成模式，这让人想起支气管肺发育不良（BPD）中描述的畸形血管结构。本研究的目的是确定临床病理相关性，生长特征和这种异常形式的移植血管生成的分子调控。研究方法：移植后4周，对来自12个可预测胎儿（15至22周妊娠）并植入SCID-米色小鼠肾包膜下空间的胎肺异种移植物进行形态学、血管形成、增殖活性和基因表达分析。结果：在60/230（26%）异种移植物中观察到局灶丛形成血管生成（PFA）。PFA的特点是一个复杂的网络曲折的非发芽血管结构与低内皮细胞增殖活性，提示内陷型血管生成。PFA的发生与胎龄或分娩与植入之间的时间间隔无关。PFA优先定位于相对缺氧的中央包膜下区。微阵列分析表明，PFA移植区域中15个基因的表达改变，其中7个是已知的血管生成/淋巴管生成调节因子，5个是已知的缺氧诱导基因。qRT-PCR分析证实了PFA在移植区域中SULF 2、IGF 2和HMOX 1的显著上调。结论：这些在人胎肺离体的观察表明，小管后肺可以从萌芽血管生成转变为异常的内陷型血管生成，这是高度联想到BPD相关的血管生成障碍。虽然间接证据表明可能与缺氧有关，但早产儿肺中这种血管生成转换的确切触发机制、分子调控和临床意义仍有待确定。
Background: Human fetal lung xenografts display an unusual pattern of non-sprouting, plexus-forming angiogenesis that is reminiscent of the dysmorphic angioarchitecture described in bronchopulmonary dysplasia (BPD). The aim of this study was to determine the clinicopathological correlates, growth characteristics and molecular regulation of this aberrant form of graft angiogenesis. Methods: Fetal lung xenografts, derived from 12 previable fetuses (15 to 22 weeks' gestation) and engrafted in the renal subcapsular space of SCID-beige mice, were analyzed 4 weeks posttransplantation for morphology, vascularization, proliferative activity and gene expression. Results: Focal plexus-forming angiogenesis (PFA) was observed in 60/230 (26%) of xenografts. PFA was characterized by a complex network of tortuous nonsprouting vascular structures with low endothelial proliferative activity, suggestive of intussusceptive-type angiogenesis. There was no correlation between the occurrence of PFA and gestational age or time interval between delivery and engraftment. PFA was preferentially localized in the relatively hypoxic central subcapsular area. Microarray analysis suggested altered expression of 15 genes in graft regions with PFA, of which 7 are known angiogenic/lymphangiogenic regulators and 5 are known hypoxia-inducible genes. qRT-PCR analysis confirmed significant upregulation of SULF2, IGF2, and HMOX1 in graft regions with PFA. Conclusion: These observations in human fetal lungs ex vivo suggest that postcanalicular lungs can switch from sprouting angiogenesis to an aberrant intussusceptive-type of angiogenesis that is highly reminiscent of BPD-associated dysangiogenesis. While circumstantial evidence suggests hypoxia may be implicated, the exact triggering mechanisms, molecular regulation and clinical implications of this angiogenic switch in preterm lungs in vivo remain to be determined.