VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways
VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways
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DOI：
10.1006/mvre.2001.2338
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发表时间：
2001-11-01
影响因子：
3.1
通讯作者：
Durán, WN
中科院分区：
文献类型：
--
作者：
Lal, BK;Varma, S;Durán, WN
VEGF是血管通透性的关键调节因子。然而，其信号通路尚不完全清楚。我们利用人脐静脉内皮细胞（HUVEC）验证了VEGF通过激活PXB/akt、NOS和MAP激酶依赖通路来调节内皮细胞（EC）通透性的假设。在基线和VEGF作用后0.034、0.068、1、10和100 nM时，通过fitc -葡聚糖70 kda通量测量EC单层的通透性。VEGF以剂量依赖性方式增加HUVEC对fitc -葡聚糖的通透性。VEGF （I nM）使通透性从3.9 X 10(-6) +/- 0.7 X 10（-6）增加到14.0 X 10(-6) +/- 1.7 X 10(-6) cm/s（平均+/- SEM； P < 0.001）。在1、10和100 nM wortmannin （PI 3-激酶抑制剂）治疗后，还评估了通透性的变化；0.01、0.1、1.0 nM LY294002 （PI 3-激酶抑制剂）；200 muM L-NMMA （NOS抑制剂）；2.7 muM AG126 （p42/44（MAPK）抑制剂）；0.006、0.06和0.6 muM SB203580 （p38（MAPK）抑制剂）。所有抑制剂均阻断vegf诱导的通透性改变。我们的数据表明(1)VEGF以剂量依赖的方式增加EC单层的通透性；(2)VEGF诱导的通透性是通过PI-3激酶- pkb、NOS和map -激酶信号级联介导的。这些观察结果表明，与炎症和血管疾病相关的微血管高通透性是由这些EC信号通路的激活介导的。(C) 2001学术出版社。
VEGF is a key regulator of vascular permeability. However, its signaling pathways are incompletely understood. We tested the hypothesis that VEGF regulates endothelial cell (EC) permeability by activating PXB/akt, NOS, and MAP kinase dependent pathways using human umbilical vein EC (HUVEC). Permeability was measured from FITC-dextran 70-kDa flux across the EC monolayer at baseline and after VEGF at 0.034, 0.068, 1, 10, and 100 nM. VEGF increased HUVEC permeability to FITC-dextran in a dose-dependent manner. VEGF (I nM) increased permeability from 3.9 X 10(-6) +/- 0.7 X 10(-6) to 14.0 X 10(-6) +/- 1.7 X 10(-6) cm/s (mean +/- SEM; P < 0.001). Permeability changes were also assessed after treatment with 1, 10, and 100 nM wortmannin (PI 3-kinase inhibitor); 0.01, 0.1, and 1.0 nM LY294002 (PI 3-kinase inhibitor); 200 muM L-NMMA (NOS inhibitor); 2.7 muM AG126 (p42/44(MAPK) inhibitor); and 0.006, 0.06, and 0.6 muM SB203580 (p38(MAPK) inhibitor). All inhibitors blocked VEGF-induced permeability changes. Our data demonstrate that (1) VEGF increases permeability of EC monolayers in a dose-dependent fashion, and (2) VEGF-induced permeability is mediated through PI-3 kinase-PKB, NOS, and MAP-kinase signaling cascades. These observations suggest that microvascular hyperpermeability associated with inflammation and vascular disease is mediated by activation of these EC signaling pathways. (C) 2001 Academic Press.