Pigment epithelium-derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol.
Pigment epithelium-derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol.
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色素上皮衍生因子/血管内皮生长因子比值对婴儿血管瘤的自然消退和普萘洛尔的治疗效果起着至关重要的作用
DOI：
10.1111/cas.13611
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发表时间：
2018-06
期刊：
影响因子：
5.7
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Zhu L;Xie J;Liu Z;Huang Z;Huang M;Yin H;Qi W;Yang Z;Zhou T;Gao G;Zhang J;Yang X
婴儿血管瘤（IH）是一种由异常血管生成形成的良性肿瘤，随着时间的推移会自发消退。普萘洛尔是IH的一线治疗药物，通过下调血管内皮生长因子（VEGF）通路的活化来抑制血管生成，该通路在IH中过度活化。然而，据报道，这种治疗对10%的肿瘤无效，19%的患者在普萘洛尔治疗后复发。促血管生成因子和抗血管生成因子均调节血管生成，而色素上皮衍生因子（PEDF）是最有效的内源性抗血管生成因子。PEDF/VEGF比值控制许多血管生成过程，但其在IH中的作用以及该比值与普萘洛尔之间的关系仍不清楚。本研究结果表明，PEDF/VEGF的比例增加，在退化期的IH相比，增殖期。类似地，在用磁珠分离的血管瘤衍生的内皮细胞（HemEC）中，增加PEDF/VEGF比率抑制增殖、迁移和管形成，并促进凋亡。从机制上讲，VEGF受体（VEGFR 1和VEGFR 2）和PEDF受体（层粘连蛋白受体，LR）在IH组织和HemEC中高度表达，PEDF通过与LR结合抑制HemEC功能。有趣的是，我们发现普萘洛尔增加了PEDF/VEGF的比例，但这是通过降低VEGF表达而不是如预期的那样通过上调PEDF来实现的。此外，PEDF和普萘洛尔的组合对HemEC具有更好的抑制作用。因此，我们的研究结果表明，PEDF/VEGF比率在IH的自发消退中起着关键作用，PEDF和普萘洛尔的组合可能是普萘洛尔耐药IH的有希望的治疗策略。
Infantile hemangioma (IH) is a benign tumor that is formed by aberrant angiogenesis and that undergoes spontaneous regression over time. Propranolol, the first‐line therapy for IH, inhibits angiogenesis by downregulating activation of the vascular endothelial growth factor (VEGF) pathway, which is hyperactivated in IH. However, this treatment is reportedly ineffective for 10% of tumors, and 19% of patients relapse after propranolol treatment. Both pro‐angiogenic and anti‐angiogenic factors regulate angiogenesis, and pigment epithelium‐derived factor (PEDF) is the most effective endogenous anti‐angiogenic factor. PEDF/VEGF ratio controls many angiogenic processes, but its role in IH and the relationship between this ratio and propranolol remain unknown. Results of the present study showed that the PEDF/VEGF ratio increased during the involuting phase of IH compared with the proliferating phase. Similarly, in hemangioma‐derived endothelial cells (HemEC), which were isolated with magnetic beads, increasing the PEDF/VEGF ratio inhibited proliferation, migration, and tube formation and promoted apoptosis. Mechanistically, the VEGF receptors (VEGFR1 and VEGFR2) and PEDF receptor (laminin receptor, LR) were highly expressed in both IH tissues and HemEC, and PEDF inhibited HemEC function by binding to LR. Interestingly, we found that propranolol increased the PEDF/VEGF ratio but did so by lowering VEGF expression rather than by upregulating PEDF as expected. Furthermore, the combination of PEDF and propranolol had a more suppressive effect on HemEC. Consequently, our results suggested that the PEDF/VEGF ratio played a pivotal role in the spontaneous regression of IH and that the combination of PEDF and propranolol might be a promising treatment strategy for propranolol‐resistant IH.
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影响因子：
9.8
作者：
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通讯作者：
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DOI：
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发表时间：
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期刊：
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作者：
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DOI：
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发表时间：
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期刊：
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