Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats - Involvement of the glucocorticoid receptor and vascular permeability factor
Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats - Involvement of the glucocorticoid receptor and vascular permeability factor
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DOI：
10.1172/jci118927
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发表时间：
1996-09-15
影响因子：
15.9
通讯作者：
Oldfield, EH
中科院分区：
文献类型：
--
作者：
Heiss, JD;Papavassiliou, E;Oldfield, EH
脑肿瘤相关脑水肿的发生是因为肿瘤毛细血管缺乏正常的血脑屏障功能；血管通透性因子（VPF，又称血管内皮生长因子，VEGF）可能是这一现象的中介。临床上，地塞米松降低脑肿瘤相关血管通透性的机制尚不清楚。我们的目的是确定地塞米松对通透性的抑制是否涉及抑制VPF的作用或表达，以及地塞米松在这种情况下的作用是否由糖皮质激素受体（GR）介导。在两种大鼠渗透性模型（皮内注射9L胶质瘤细胞条件培养基或纯化的VPF诱导的周围血管渗透性，以及植入9L胶质瘤诱导的脑内血管渗透性）中，地塞米松以剂量依赖的方式抑制了渗透性。由于9L条件培养基中80%的诱导通透性活性被抗VPF抗体去除，我们检测了地塞米松对9L细胞中VPF表达的影响。地塞米松抑制FCS和pdgf依赖性诱导的VPF表达。在所有水平（皮内、颅内和细胞培养），地塞米松效应被GR拮抗剂米非司酮（RU486）逆转。地塞米松可能通过两种gr依赖机制降低脑肿瘤相关的血管通透性：降低血管对肿瘤源性通透性因子（包括VPF）的反应，以及降低肿瘤细胞对VPF的表达。
Brain tumor-associated cerebral edema arises because tumor capillaries lack normal blood-brain barrier function; vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) is a likely mediator of this phenomenon, Clinically, dexamethasone reduces brain tumor-associated vascular permeability through poorly understood mechanisms. Our goals were to determine if suppression of permeability by dexamethasone might involve inhibition of VPF action or expression, and if dexamethasone effects in this setting are mediated by the glucocorticoid receptor (GR). In two rat models of permeability (peripheral vascular permeability induced by intradermal injection of 9L glioma cell-conditioned medium or purified VPF, and intracerebral vascular permeability induced by implanted 9L glioma), dexamethasone suppressed permeability in a dose-dependent manner. Since 80% of the permeability-inducing activity in 9L-conditioned medium was removed by anti-VPF antibodies, we examined dexamethasone effects of VPF expression in 9L cells. Dexamethasone inhibited FCS- and PDGF-dependent induction of VPF expression. At all levels (intradermal, intracranial, and cell culture), dexamethasone effects were reversed by the GR antagonist mifepristone (RU486). Dexamethasone may decrease brain tumor-associated vascular permeability by two GR-dependent mechanisms: reduction of the response of the vasculature to tumor-derived permeability factors (including VPF), and reduction of VPF expression by tumor cells.