Glucocorticoid-mediated inhibition of angiogenic changes in human endothelial cells is not caused by reductions in cell proliferation or migration.
Glucocorticoid-mediated inhibition of angiogenic changes in human endothelial cells is not caused by reductions in cell proliferation or migration.
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DOI：
10.1371/journal.pone.0014476
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发表时间：
2010-12-31
期刊：
影响因子：
3.7
通讯作者：
Hadoke PW
中科院分区：
文献类型：
--
作者：
Logie JJ;Ali S;Marshall KM;Heck MM;Walker BR;Hadoke PW
糖皮质激素介导的血管生成抑制在生理学、病理生理学和治疗中很重要。然而，糖皮质激素抑制新血管生长的机制尚未确定。这项研究提出了这样的假设：生理水平的糖皮质激素通过直接阻止内皮细胞形成管，从而抑制血管生成。使用培养的人脐静脉 (HUVEC) 和主动脉 (HAoEC) 内皮细胞来确定糖皮质激素对管状结构 (TLS) 形成以及细胞增殖（5-溴-2'-脱氧尿苷 (BrdU) 掺入）、活力（ATP 产生）和迁移（博伊登室）的影响。地塞米松或皮质醇（生理浓度）抑制基质胶上培养的内皮细胞 (EC) 中基础和前列腺素 F2α (PGF2α) 诱导的以及血管内皮生长因子 (VEGF) 刺激的 TLS 形成，而糖皮质激素受体拮抗剂 RU38486 可阻断这种作用。糖皮质激素对 EC 活力、迁移或增殖没有影响。延时成像显示皮质醇阻断 VEGF 刺激的细胞骨架重组和管形成的初始化。实时 PCR 表明，thrombospodin-1 表达增加有助于糖皮质激素介导的 TLS 形成抑制。我们的结论是，糖皮质激素直接与血管 EC 上的糖皮质激素受体相互作用，抑制 TLS 的形成。这种作用在来自两个不同血管区域的 EC 中是保守的，是由于细胞形态的改变而不是对 EC 活力、迁移或增殖的抑制，并且可能部分由血小板球蛋白-1 的诱导介导。这些发现为内源性糖皮质激素在健康和疾病中的抗血管生成作用提供了重要的见解。
Glucocorticoid-mediated inhibition of angiogenesis is important in physiology, pathophysiology and therapy. However, the mechanisms through which glucocorticoids inhibit growth of new blood vessels have not been established. This study addresses the hypothesis that physiological levels of glucocorticoids inhibit angiogenesis by directly preventing tube formation by endothelial cells. Cultured human umbilical vein (HUVEC) and aortic (HAoEC) endothelial cells were used to determine the influence of glucocorticoids on tube-like structure (TLS) formation, and on cellular proliferation (5-bromo-2′-deoxyuridine (BrdU) incorporation), viability (ATP production) and migration (Boyden chambers). Dexamethasone or cortisol (at physiological concentrations) inhibited both basal and prostaglandin F2α (PGF2α)-induced and vascular endothelial growth factor (VEGF) stimulated TLS formation in endothelial cells (ECs) cultured on Matrigel, effects which were blocked with the glucocorticoid receptor antagonist RU38486. Glucocorticoids had no effect on EC viability, migration or proliferation. Time-lapse imaging showed that cortisol blocked VEGF-stimulated cytoskeletal reorganisation and initialisation of tube formation. Real time PCR suggested that increased expression of thrombospodin-1 contributed to glucocorticoid-mediated inhibition of TLS formation. We conclude that glucocorticoids interact directly with glucocorticoid receptors on vascular ECs to inhibit TLS formation. This action, which was conserved in ECs from two distinct vascular territories, was due to alterations in cell morphology rather than inhibition of EC viability, migration or proliferation and may be mediated in part by induction of thrombospodin-1. These findings provide important insights into the anti-angiogenic action of endogenous glucocorticoids in health and disease.
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影响因子：
6
作者：
Bussolati, B;Dunk, C;Ahmed, A
通讯作者：
Ahmed, A
影响因子：
5
作者：
Luo, JC;Shin, VY;Cho, CH
通讯作者：
Cho, CH
影响因子：
9.6
作者：
GREEN, JP
通讯作者：
GREEN, JP
影响因子：
5.6
作者：
LONGENECKER, JP;KILTY, LA;JOHNSON, LK
通讯作者：
JOHNSON, LK
影响因子：
4.3
作者：
Pross, C;Farooq, MM;Gelabert, HA
通讯作者：
Gelabert, HA