VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors
VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors
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DOI：
10.1160/th03-02-0084
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发表时间：
2003-08-01
影响因子：
6.7
通讯作者：
Lugnier, C
中科院分区：
文献类型：
--
作者：
Favot, L;Keravis, T;Lugnier, C
响应于VEGF的内皮细胞的迁移和增殖在与诸如动脉粥样硬化、糖尿病和肿瘤发展的病理相关的血管生成中起重要作用。已显示内皮细胞中cAMP的升高抑制生长因子诱导的增殖。我们的假设是cAMP特异性磷酸二酯酶（PDE）的失活将抑制血管生成。本研究的目的是评价PDE抑制剂对体外和体内血管生成的影响，分别使用人脐静脉内皮细胞（HUVEC）和鸡胚绒毛尿囊膜（CAM）模型。在此，我们报告：1）人脐静脉内皮细胞表达PDE 2、PDE 3、PDE 4和PDES，2）PDE 2选择性抑制剂EHNA（20 μ M）和PDE 4选择性抑制剂RP 73401（10 μ M）能增加人脐静脉内皮细胞内cAMP水平，3）EHNA和RP 73401能抑制VEGF刺激的人脐静脉内皮细胞增殖、细胞周期进程和迁移; 4）这些体外作用可以通过用cAMP类似物8-Br-cAMP（600 μ M）处理HUVEC来模拟; 5）只有EHNA和RP 73401的联合抑制体内血管生成，表明迁移和增殖都必须被抑制。这些数据有力地表明，PDE 2和PDE 4代表了病理性血管生成中新的潜在治疗靶点。
Migration and proliferation of endothelial cells in response to VEGF play an important role in angiogenesis associated to pathologies such as atherosclerosis, diabetes and tumor development. Elevation of cAMP in endothelial cells has been shown to inhibit growth factor-induced proliferation. Our hypothesis was that inactivation of cAMP-pecific phosphodiesterases (PDEs) would inhibit angiogenesis. The purpose of this study was to evaluate the effect of PDE inhibitors on in vitro and in vivo angiogenesis, using human umbilical vein endothelial cell (HUVEC) and chick chorioallantoic membrane (CAM) models respectively. Here, we report that: 1) PDE2, PDE3, PDE4 and PDES are expressed in HUVEC; 2) EHNA (20 muM), PDE2 selective inhibitor, and RP73401 (10 muM), PDE4 selective inhibitor, are able to increase the intracellular cAMP level in HUVEC; 3) EHNA and RP73401 are able to inhibit proliferation, cell cycle progression and migration of HUVEC stimulated by VEGF; 4) these in vitro effects can be mimic by treating HUVEC with the cAMP analogue, 8-Br-cAMP (600 muM); 5) only the association of EHNA and RP73401 inhibits in vivo angiogenesis, indicating that both migration and proliferation must be inhibited. These data strongly suggest that PDE2 and PDE4 represent new potential therapeutic targets in pathological angiogenesis.