Department of Emergency Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Xicheng, Beijing, 100050, China.
Neurocrit Care. 2021 Oct;35(2):379-388. doi: 10.1007/s12028-020-01166-0. Epub 2021 Jan 5.
The hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF)/VEGF receptor subtype 2 (VEGFR-2) pathway has been implicated in ischemia/reperfusion injury. The aim of this study was to clarify whether whole-body hypothermic targeted temperature management (HTTM) inhibits the HIF-1α/VEGF/VEGFR-2 pathway in a swine model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR).
Twenty-four domestic male Beijing Landrace pigs were used in this study. CA was electrically induced with ventricular fibrillation and left untreated for 8 min. Return of spontaneous circulation (ROSC) was achieved in 16 pigs, which were randomly assigned either to normothermia at 38 °C or to HTTM at 33 °C (each group: n = 8). HTTM was intravascularly induced immediately after ROSC. The core temperature was reduced to 33 °C and maintained for 12 h after ROSC. The serum levels of HIF-1α, VEGF, VEGFR-2, and neuron-specific enolase (NSE) were measured with enzyme immunoassay kits 0.5, 6, 12, and 24 h after ROSC. The expression of HIF-1α, VEGF, and VEGFR-2 in cerebral cortical tissue was measured by RT-PCR and Western blot analysis 24 h after ROSC. Neurological deficit scores and brain cortical tissue water content were evaluated 24 h after ROSC.
The serum levels of HIF-1α, VEGF, and VEGFR-2 were significantly increased under normothermia within 24 h after ROSC. However, these increases were significantly reduced by HTTM. HTTM also decreased cerebral cortical HIF-1α, VEGF, and VEGFR-2 mRNA and protein expression 24 h after ROSC (all p < 0.05). HTTM pigs had better neurological outcomes and less brain edema than normothermic pigs.
The HIF-1α/VEGF/VEGFR-2 system is activated following CA and CPR. HTTM protects against cerebral injury after ROSC, which may be part of the mechanism by which it inhibits the expression of components of the HIF-1α/VEGF/VEGFR-2 signaling pathway.
缺氧诱导因子-1α（HIF-1α）/血管内皮生长因子（VEGF）/VEGF 受体亚型 2（VEGFR-2）通路与缺血再灌注损伤有关。本研究旨在阐明全身低温靶向体温管理（HTTM）是否会抑制心脏骤停（CA）和心肺复苏（CPR）猪模型中的 HIF-1α/VEGF/VEGFR-2 通路。
本研究使用 24 头国内雄性北京长白猪。通过心室颤动诱导 CA，且不进行处理 8 分钟。16 头猪恢复自主循环（ROSC），随机分为常温组（38°C，n = 8）和 HTTM 组（33°C，n = 8）。HTTM 在 ROSC 后立即进行血管内诱导。核心温度降至 33°C，ROSC 后维持 12 小时。在 ROSC 后 0.5、6、12 和 24 小时，使用酶联免疫吸附试剂盒测量血清 HIF-1α、VEGF、VEGFR-2 和神经元特异性烯醇化酶（NSE）水平。在 ROSC 后 24 小时，通过 RT-PCR 和 Western blot 分析测量脑皮质组织中 HIF-1α、VEGF 和 VEGFR-2 的表达。在 ROSC 后 24 小时，评估神经功能缺损评分和脑皮质组织含水量。
在 ROSC 后 24 小时内，常温下血清 HIF-1α、VEGF 和 VEGFR-2 水平显著升高。然而，HTTM 显著降低了这些升高。HTTM 还降低了 ROSC 后 24 小时脑皮质 HIF-1α、VEGF 和 VEGFR-2 mRNA 和蛋白表达（均 p < 0.05）。HTTM 猪的神经功能预后优于常温猪，脑水肿较少。
CA 和 CPR 后 HIF-1α/VEGF/VEGFR-2 系统被激活。HTTM 可防止 ROSC 后脑损伤，这可能是其抑制 HIF-1α/VEGF/VEGFR-2 信号通路成分表达的机制之一。
