目的：Notch信号对胚胎发育、血管损伤修复、肿瘤生长过程中的血管重构发挥了重要作用，但对肺动脉高压肺血管重构研究很少，本研究旨在探讨抑制Notch信号对血管紧张素Ⅱ（AngII）诱导的肺血管重构的影响。方法：采用AngⅡ持续刺激培养7 d的肺动脉血管条，测定血管管壁厚度及血管壁细胞增殖细胞核抗原（PCNA）和caspase-3阳性率。同时部分血管条还加入γ-分泌酶抑制剂DAPT抑制Notch信号，测定血管条Notch 1~4 受体及其下游转录因子HERP1、HERP2 mRNA水平。结果：AngⅡ持续刺激血管7 d，血管壁厚度增加近50%，伴有血管壁细胞PCNA阳性率升高和caspase-3阳性率降低（P＜0.05）。加入DAPT后，血管条Notch 1~4受体mRNA水平无明显改变，但HERP 1、2 mRNA水平降低（P＜0.05），管壁厚度、PCNA和caspase-3阳性率的改变程度明显降低（P＜0.05）。结论：抑制Notch信号能抑制AngⅡ诱导的肺血管重构，可能成为肺动脉高压治疗的一个新思路。
Abstract
OBJECTIVE: It is known that Notch signal is very important to vascular remodeling during the process of embryonic development, vessel repair and tumor growth, but there are few studies about pulmonary vascular remodeling in pulmonary hypertension. This study was to explore the effect of inhibiting Notch signal on pulmonary vascular remodeling induced by angiotensin Ⅱ. METHODS: Vessel strips taken from healthy Wistar rats were co-cultured with extrogenous angiotensin Ⅱand the potent smooth muscle cell proliferation stimulators for 7 days. Vascular wall thickness, proliferating cell nuclear antigen (PCNA) positive cell rate and caspase-3 positive cell rate were examined in vessel strips. Then some vessel strips were cultured with angiotensin Ⅱ and γ-secretase inhibitor DAPT, a Notch signaling inhibitor for 7 days. The levels of Notch 1 to 4 receptor and HERP1/2 mRNA were ascertained by FQ-PCR. RESULTS: Angiotensin Ⅱstimulation in the cultured normal pulmonary arteries resulted in an increase in the vascular medial thickness by nearly 50%, and a significant increase in the PCNA positive cell rate and a decrease in the caspase-3 positive cell rate. DAPT treatment did not result in the alterations of Notch 1 to 4 receptor levels, but decreased remarkably HERP1 and HERP2 mRNA expression. DAPT treatment also decreased angiotensin Ⅱ-induced vascular medial thickness and PCNA positive cell rate and increased caspase-3 positive cell rate. CONCLUSIONS: Inhibiting Notch signal by γ-secretase inhibitor may lead to the suppression of pulmonary vascular remodeling induced by angiotensin Ⅱ, suggesting that the inhibition of Notch signal pathway might be a novel strategy for the treatment of pulmonary hypertension.
关键词
Notch信号 /
血管紧张素 /
肺 /
血管重构 /
大鼠
Key words
Notch signal /
Angiotensin /
Pulmonary /
Vascular remodeling /
Rats
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