Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
PLoS One. 2013 Jul 24;8(7):e68922. doi: 10.1371/journal.pone.0068922. Print 2013.
It is now widely recognized that radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiovascular damage although the underlying mechanisms are not fully elucidated. There is increasing evidence that microvascular damage is involved. Endoglin, an accessory receptor for TGF-β1, is highly expressed in damaged endothelial cells and may play a crucial role in cell proliferation and revascularization of damaged heart tissue. We have therefore specifically examined the role of endoglin in microvascular damage and repair in the irradiated heart.
MATERIALS & METHODS: A single dose of 16 Gy was delivered to the heart of adult Eng(+/+) or Eng(+/-) mice and damage was evaluated at 4, 20 and 40 weeks, relative to age-matched controls. Gated single photon emission computed tomography (gSPECT) was used to measure cardiac geometry and function, and related to histo-morphology, microvascular damage (detected using immuno- and enzyme-histochemistry) and gene expression (detected by microarray and real time PCR).
Genes categorized according to known inflammatory and immunological related disease were less prominently regulated in irradiated Eng(+/-) mice compared to Eng(+/+) littermates. Fibrosis related genes, TGF-β1, ALK 5 and PDGF, were only upregulated in Eng(+/+) mice during the early phase of radiation-induced cardiac damage (4 weeks). In addition, only the Eng(+/+) mice showed significant upregulation of collagen deposition in the early fibrotic phase (20 weeks) after irradiation. Despite these differences in gene expression, there was no reduction in inflammatory invasion (CD45+cells) of irradiated Eng(+/-) hearts. Microvascular damage (microvascular density, alkaline phosphatase and von-Willebrand-Factor expression) was also similar in both strains.
Eng(+/-) mice displayed impaired early inflammatory and fibrotic responses to high dose irradiation compared to Eng(+/+) littermates. This did not result in significant differences in microvascular damage or cardiac function between the strains.
现在人们广泛认识到，胸部和胸壁肿瘤的放射治疗增加了长期心血管损伤的风险，尽管其潜在机制尚未完全阐明。越来越多的证据表明微血管损伤与此有关。内皮糖蛋白（Eng）是 TGF-β1 的辅助受体，在受损的内皮细胞中高度表达，可能在受损心脏组织的细胞增殖和再血管化中发挥关键作用。因此，我们专门研究了内皮糖蛋白在放射心脏中的微血管损伤和修复中的作用。
在成年 Eng(+/+)或 Eng(+/-)小鼠的心脏中单次给予 16Gy 的剂量，并相对于同龄对照评估 4、20 和 40 周时的损伤。门控单光子发射计算机断层扫描（gSPECT）用于测量心脏几何形状和功能，并与组织形态学、微血管损伤（使用免疫组织化学和酶组织化学检测）和基因表达（通过微阵列和实时 PCR 检测）相关联。
根据已知的炎症和免疫学相关疾病进行分类的基因在放射 Eng(+/-)小鼠中比 Eng(+/+)同窝仔鼠的调节作用不明显。纤维化相关基因，TGF-β1、ALK 5 和 PDGF，仅在放射诱导的心脏损伤早期（4 周）在 Eng(+/+)小鼠中上调。此外，只有 Eng(+/+)小鼠在照射后早期纤维化阶段（20 周）显示胶原沉积显著上调。尽管基因表达存在这些差异，但放射 Eng(+/-)心脏的炎症浸润（CD45+细胞）并没有减少。两种品系的微血管损伤（微血管密度、碱性磷酸酶和血管性血友病因子表达）也相似。
与 Eng(+/+)同窝仔鼠相比，Eng(+/-)小鼠对高剂量辐射表现出受损的早期炎症和纤维化反应。这并没有导致两种品系之间的微血管损伤或心脏功能出现显著差异。
