SFlt-1 elevates blood pressure by augmenting endothelin-1-mediated vasoconstriction in mice.
SFlt-1 elevates blood pressure by augmenting endothelin-1-mediated vasoconstriction in mice.
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DOI：
10.1371/journal.pone.0091897
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
van den Born BJ
中科院分区：
文献类型：
--
作者：
Amraoui F;Spijkers L;Hassani Lahsinoui H;Vogt L;van der Post J;Peters S;Afink G;Ris-Stalpers C;van den Born BJ
清除血管内皮生长因子（VEGF）升高接受抗血管生成治疗的患者的血压（BP）。类似地，可溶性受体fms样酪氨酸激酶-1（sFlt-1）对循环VEGF的抑制是先兆子痫血压升高的基础。两种表型的特征在于内皮素-1（ET-1）的产生增加，表明ET-1在抗血管生成性高血压中的作用。我们的目的是评估VEGF抑制对ET-1诱导的收缩性和下游ET-1信号传导的影响。用sFlt-1或媒介物处理雄性C57 BL/6 N小鼠，并通过尾套评估BP。与媒介物处理的对照相比，sFlt-1处理的小鼠的平均动脉压显著增加（N = 11-12，p<0.05）。 处死后，分离颈动脉和肠系膜动脉进行等长张力测量。ET-1诱导的收缩在载体和sFlt-1处理的小鼠的肠系膜动脉中相似，但与对照相比，在sFlt-1处理的小鼠的颈动脉段中增强（N = 9-10，p<0.05）。 环氧化酶（考克斯）抑制剂吲哚美辛（N = 9-10，p<0.05）可完全消除颈动脉节段中增加的收缩，这表明增强的藜芦醇介导的血管收缩。 这与sFlt-1处理的小鼠中向促收缩ETB信号传导的转变有关，可能解释了ET-1诱导的胰高血糖素介导的血管收缩增加。与体外研究结果一致，sFlt-1诱导的BP升高可以通过口服高剂量的考克斯抑制剂阿司匹林（N = 7）或吡考他胺（N = 9）（一种双重血栓烷A2合酶抑制剂和受体拮抗剂）在体内预防。 VEGF抑制增强对ET-1的升压反应。ET-1下游的环氧合酶-血栓烷信号通路可能是VEGF抑制过程中防止血压升高的可能靶点。
Scavenging of vascular endothelial growth factor (VEGF) elevates blood pressure (BP) in patients receiving anti-angiogenic therapy. Similarly, inhibition of circulation VEGF by its soluble receptor fms-like tyrosine kinase-1 (sFlt-1) underlies BP elevation in pre-eclampsia. Both phenotypes are characterized by augmented production of endothelin-1 (ET-1), suggesting a role for ET-1 in anti-angiogenic hypertension. We aimed to assess the effect of VEGF inhibition on ET-1-induced contractility and downstream ET-1 signaling. Male C57BL/6N mice were treated with either sFlt-1 or vehicle and BP was assessed via tail-cuff. Mean arterial pressure of sFlt-1-treated mice markedly increased compared to vehicle-treated controls (N = 11–12, p<0.05). After sacrifice, carotid and mesenteric arteries were isolated for isometric tension measurements. ET-1-induced contractions were similar in mesenteric arteries of vehicle and sFlt-1-treated mice, but augmented in carotid segments of sFlt-1-treated mice compared to controls (N = 9–10, p<0.05). The increased contraction in carotid segments could be completely abrogated by the cyclooxygenase (COX) inhibitor indomethacin (N = 9–10, p<0.05), indicating heightened prostaglandin-mediated vasoconstriction. This was associated with a shift towards procontractile ETB signaling in sFlt-1-treated mice, possibly explaining the increased ET-1-induced prostaglandin-mediated vasoconstriction. In line with the ex vivo findings, sFlt-1-induced BP elevation could be prevented in vivo by oral treatment with either a high-dose of the COX inhibitor aspirin (N = 7) or with picotamide (N = 9), a dual thromboxane A2 synthase inhibitor and receptor antagonist. VEGF inhibition augments the pressor response to ET-1. The cyclooxygenase-thromboxane signaling route downstream of ET-1 might be a possible target to prevent BP elevation during VEGF inhibition.
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