VEGF signalling enhances lesion burden in KRIT1 deficient mice
VEGF signalling enhances lesion burden in KRIT1 deficient mice
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DOI：
10.1111/jcmm.14773
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发表时间：
2019-11-20
影响因子：
5.3
通讯作者：
Glading, Angela J.
中科院分区：
文献类型：
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作者：
DiStefano, Peter V.;Glading, Angela J.
CCM发病机制的确切分子机制仍然是一个复杂而有争议的话题。我们之前的研究表明，在KRIT1缺失的内皮细胞中存在一个重要的VEGF信号环。由于VEGF是许多血管病变的主要介质，我们想知道KRIT1缺失下游VEGF信号的增加是否参与CCM的形成。利用诱导的KRIT1内皮特异性敲除小鼠模型CCM，我们发现VEGFR2激活在小鼠CCM发病机制中起作用。使用特定的抑制剂SU5416抑制VEGFR2，可以显著减少形成的病变数量，并略微降低平均病变大小。值得注意的是，VEGFR2抑制也减少了病变出血的出现，这是由邻近组织中游离铁的存在所表明的。游离铁的存在与骨骼肌和脑微血管通透性增加相关，SU5416治疗完全逆转了这一现象。最后，我们发现VEGFR2激活是KRIT1、CCM2和CCM3功能丧失的常见下游后果，尽管VEGFR2激活的机制可能各不相同。因此，我们的研究清楚地表明，KRIT1缺失下游的VEGFR2激活增强了小鼠CCM形成的严重程度，并表明靶向VEGF信号可能是未来治疗CCM的潜在方法。
The exact molecular mechanisms underlying CCM pathogenesis remain a complicated and controversial topic. Our previous work illustrated an important VEGF signalling loop in KRIT1 depleted endothelial cells. As VEGF is a major mediator of many vascular pathologies, we asked whether the increased VEGF signalling downstream of KRIT1 depletion was involved in CCM formation. Using an inducible KRIT1 endothelial-specific knockout mouse that models CCM, we show that VEGFR2 activation plays a role in CCM pathogenesis in mice. Inhibition of VEGFR2 using a specific inhibitor, SU5416, significantly decreased the number of lesions formed and slightly lowered the average lesion size. Notably, VEGFR2 inhibition also decreased the appearance of lesion haemorrhage as denoted by the presence of free iron in adjacent tissues. The presence of free iron correlated with increased microvessel permeability in both skeletal muscle and brain, which was completely reversed by SU5416 treatment. Finally, we show that VEGFR2 activation is a common downstream consequence of KRIT1, CCM2 and CCM3 loss of function, though the mechanism by which VEGFR2 activation occurs likely varies. Thus, our study clearly shows that VEGFR2 activation downstream of KRIT1 depletion enhances the severity of CCM formation in mice, and suggests that targeting VEGF signalling may be a potential future therapy for CCM.