AT1 Receptor Antagonism Is Proangiogenic in the Brain: BDNF a Novel Mediator
AT1 Receptor Antagonism Is Proangiogenic in the Brain: BDNF a Novel Mediator
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DOI：
10.1124/jpet.112.197483
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发表时间：
2013-02-01
影响因子：
3.5
通讯作者：
Fagan, Susan C.
中科院分区：
文献类型：
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作者：
Alhusban, Ahmed;Kozak, Anna;Fagan, Susan C.
坎地沙坦是一种血管紧张素 II 1 型受体阻滞剂 (ARB)，已被证明可以限制缺血性中风并改善中风结果。在实验性中风中，坎地沙坦诱导促血管生成作用，部分归因于血管内皮生长因子。脑源性神经营养因子 (BDNF) 是神经营养蛋白家族的一员，据报道具有血管生成作用，并在中风后的恢复中发挥重要作用。本研究的目的是确定 BDNF 在高血压条件下大脑中坎地沙坦的促血管生成作用中的作用。因此，自发性高血压大鼠接受坎地沙坦治疗，并收集脑组织样本用于定量 BDNF 表达。此外，人脑微血管内皮细胞单独用低剂量（1fM）或高剂量（1μM）血管紧张素II或与坎地沙坦（0.16μM）联合处理，以评估坎地沙坦治疗和BDNF对内皮细胞行为的影响。坎地沙坦显着增加 SHR 中 BDNF 的表达（P < 0.05）。此外，坎地沙坦逆转了 1-μM 剂量 AngII 的抗血管生成作用 (P - 0.0001)。通过中和 BDNF 的作用，观察到的坎地沙坦的作用被消除。 AT2 拮抗剂 PD-123319 治疗显着减少内皮细胞中管状形成。 AT2刺激诱导BDNF表达和迁移（P，0.05）。总之，坎地沙坦对血管紧张素 II 处理的脑微血管内皮细胞发挥促血管生成作用。这种反应归因于 BDNF 表达增加，并通过刺激 AT2 受体介导。
Candesartan is an angiotensin II type 1 receptor blocker (ARB) that has been to shown to limit ischemic stroke and improve stroke outcome. In experimental stroke, candesartan induces a proangiogenic effect that is partly attributable to vascular endothelial growth factor. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has been reported to have angiogenic effects and play an important role in recovery after stroke. The purpose of this investigation was to determine the role of BDNF in the proangiogenic effect of candesartan in the brain under hypertensive conditions. Accordingly, spontaneously hypertensive rats were treated with candesartan, and brain tissue samples were collected for quantification of BDNF expression. In addition, human cerebro-microvascular endothelial cells were treated with either low-dose (1 fM) or high-dose (1 mu M) angiotensin II alone or in combination with candesartan (0.16 mu M) to assess the effect of candesartan treatment and BDNF involvement in the behavior of endothelial cells. Candesartan significantly increased the expression of BDNF in the SHR (P < 0.05). In addition, candesartan reversed the antiangiogenic effect of the 1-mu M dose of AngII (P - 0.0001). The observed effects of candesartan were ablated by neutralizing the effects of BDNF. Treatment with the AT2 antagonist PD-123319 significantly reduced tube-like formation in endothelial cells. AT2 stimulation induced the BDNF expression and migration (P, 0.05). In conclusion, candesartan exerts a proangiogenic effect on brain microvascular endothelial cells treated with angiotensin II. This response is attributable to increased BDNF expression and is mediated through stimulation of the AT2 receptor.