The role of β-adrenergic receptor signaling in the proliferation of hemangioma-derived endothelial cells.
The role of β-adrenergic receptor signaling in the proliferation of hemangioma-derived endothelial cells.
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DOI：
10.1186/1747-1028-8-1
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发表时间：
2013-01-03
期刊：
影响因子：
2.3
通讯作者：
Xu T
中科院分区：
文献类型：
--
作者：
Ji Y;Chen S;Li K;Xiao X;Zheng S;Xu T
摘要婴儿血管瘤是一种良性的血管肿瘤，其起因于血管内皮细胞的异常增生及血管新生的增强。近年来，研究发现普萘洛尔对IH的治疗有效，提示β-肾上腺素能受体（β-ARs）在IH的发病机制中可能起重要作用。在本研究中，我们研究了与血管瘤源性内皮细胞（HemEC）增殖相关的β-肾上腺素能信号。结果表明，β1-AR和β2-AR在HemEC中均有表达。用异丙肾上腺素刺激β-AR可诱导细胞增殖和第二信使cAMP水平升高。异丙肾上腺素的促细胞增殖作用可被β1选择性拮抗剂所阻断，β2选择性拮抗剂的作用效果更明显，其作用机制是使细胞周期阻滞于G 0/G1期，并降低cyclin D1、CDK-4、CDK-6和磷酸化Rb的表达。用VEGFR-2或ERK抑制剂预处理细胞也阻止了异丙肾上腺素介导的细胞增殖。与β-AR和VEGFR-2参与HemEC反应一致，β-AR拮抗剂和VEGFR-2抑制剂显著减弱异丙肾上腺素诱导的ERK磷酸化。异丙肾上腺素处理后，VEGF-A的表达和VEGFR-2的活性显著增加，且呈β2-AR依赖性。我们已经证明，ERK通路中的β-AR的激活可能是促进HemEC生长的重要机制。此外，β-AR的刺激可反式激活VEGFR-2信号传导并进一步增加HemEC增殖。
Infantile hemangioma (IH) is a benign vascular neoplasm that arises from the abnormal proliferation of endothelial cells and enhanced angiogenesis. Recently, propranolol has been found to be effective in the management of IH, suggesting that β-adrenergic receptors (β-ARs) may play an important role in the pathogenesis of IH. In the present study, we investigated the β-adrenergic signaling that is associated with hemangioma-derived endothelial cell (HemEC) proliferation. The results showed that both β1- and β2-ARs were expressed in HemECs. Stimulation of the β-ARs by isoprenaline induced cell proliferation and elevation of second messenger cAMP levels. The proliferation-promoting action of isoprenaline was abolished by a β1-selective antagonist and was more effectively abolished by a β2-selective antagonist; the mechanism for the action of the antagonists was a G0/G1 phase cell cycle arrest which was associated with decreased cyclin D1, CDK-4, CDK-6 and phospho-Rb expression. Pre-treatment of the cells with VEGFR-2 or ERK inhibitors also prevented the isoprenaline-mediated proliferation of cells. In agreement with the involvement of β-ARs and VEGFR-2 in the HemEC response, β-AR antagonists and the VEGFR-2 inhibitor significantly attenuated isoprenaline-induced ERK phosphorylation. Moreover, treating the cells with isoprenaline markedly increased VEGF-A expression and VEGFR-2 activity in a β2-AR-dependent manner. We have demonstrated that the activation of the β-ARs in the ERK pathway may be important mechanisms in promoting HemEC growth. Furthermore, stimulation of the β-AR may transactivate VEGFR-2 signaling and further increase HemEC proliferation.
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DOI：
10.1056/nejmoa0903036
发表时间：
2010-03-18
期刊：
The New England journal of medicine
影响因子：
--
作者：
Greenberger S;Boscolo E;Adini I;Mulliken JB;Bischoff J
通讯作者：
Bischoff J
影响因子：
--
作者：
Fuchsmann, Carine;Quintal, Marie-Claude;Froehlich, Patrick
通讯作者：
Froehlich, Patrick
影响因子：
--
作者：
George, ME;Sharma, V;Nopper, AJ
通讯作者：
Nopper, AJ
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
13.7
作者：
Goyal, R;Watts, P;Gregory, JW
通讯作者：
Gregory, JW