VEGFR-3+单核细胞对高血压小鼠左心室重塑的影响

doi:10.11958/20221051

天津医药 ›› 2023, Vol. 51 ›› Issue (2): 144-148.doi: 10.11958/20221051

VEGFR-3⁺单核细胞对高血压小鼠左心室重塑的影响

杨国红¹(), 余芳芳¹, 蔡伟¹, 牛秀珑¹, 张芯¹, 赵季红¹, 李玉明², 陈少伯¹^,^△()

1 中国人民武装警察部队特色医学中心，高原高寒环境及心血管病防治研究所，天津市心血管重塑与靶器官损伤重点实验室（邮编300162）
2 泰达国际心血管病医院

收稿日期:2022-07-04 修回日期:2022-08-19 出版日期:2023-02-15 发布日期:2023-02-24
通讯作者: ^△E-mail：chensbwj@126.com
作者简介:杨国红（1981），男，副主任医师，主要从事高血压及冠心病的基础与临床方面研究。E-mail：hong-20020@163.com
基金资助:
国家自然科学金资助项目(81600328);天津市自然科学基金资助项目(16JCQNJC11800);天津市科技重大专项资助项目(15ZXJZSY00010)

Effects of peripheral blood VEGFR-3⁺ monocytes on left ventricular remodeling in mice with hypertension

YANG Guohong¹(), YU Fangfang¹, CAI Wei¹, NIU Xiulong¹, ZHANG Xin¹, ZHAO Jihong¹, LI Yuming², CHEN Shaobo¹^,^△()

1 Institute of Prevention and Treatment of Cardiovascular Diseases in Alpine Environment of Plateau, Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury, Characteristic Medical Center of the Chinese People’s Armed Police Forces, Tianjin 300162, China
2 TEDA International Cardiovascular Hospital

Received:2022-07-04 Revised:2022-08-19 Published:2023-02-15 Online:2023-02-24
Contact: ^△E-mail：chensbwj@126.com

杨国红, 余芳芳, 蔡伟, 牛秀珑, 张芯, 赵季红, 李玉明, 陈少伯. VEGFR-3⁺单核细胞对高血压小鼠左心室重塑的影响[J]. 天津医药, 2023, 51(2): 144-148.

YANG Guohong, YU Fangfang, CAI Wei, NIU Xiulong, ZHANG Xin, ZHAO Jihong, LI Yuming, CHEN Shaobo. Effects of peripheral blood VEGFR-3⁺ monocytes on left ventricular remodeling in mice with hypertension[J]. Tianjin Medical Journal, 2023, 51(2): 144-148.

摘要/Abstract

摘要：

目的探讨高血压小鼠外周血血管内皮生长因子受体（VEGFR）-3⁺单核细胞对高盐诱导的高血压性左心室重塑的影响。方法将6周龄雄性C57BL/6小鼠随机分为正常盐饮食组（0.5% NaCl，NS组）、高盐饮食组（8% NaCl，HS组）、HS+N-硝基-L-精氨酸甲酯（L-NAME）组（HS+L组）以及HS+L-NAME+外周血VEGFR-3⁺单核细胞（PBMV）干预组（HS+L+PBMV组），在饮食干预第9~12周对高血压小鼠进行PBMV干预。所有小鼠以标准的尾压法测定无创尾压；利用Vevo 2100超声影像系统测定心脏结构和功能；荧光定量PCR检测小鼠心肌组织张力应答增强子结合蛋白（TonEBP）及淋巴管内皮细胞标志物mRNA表达水平；以Masson染色观察心肌组织纤维化程度；以麦芽胚凝集素（WGA）荧光染色计算心肌细胞横截面积（CSA）。结果干预结束时，HS+L组收缩压显著高于其他3组（P<0.05）；HS+L+PBMV组TonEBP的mRNA水平低于HS+L组，与淋巴内皮细胞相关的标志物VEGF-C、Prox-1、Podoplanin、LYVE-1的mRNA表达水平显著高于HS+L组（P<0.05）；心脏超声结果显示，HS+L+PBMV组左心室舒张末期内径（LVEDD）及左心室后壁厚度（LVPWT）显著低于HS+L组，左心室射血分数（LVEF）及左心室缩短分数（LVFS）显著高于HS+L组（P<0.05）；病理学结果显示，HS+L+PBMV组CVF及CSA明显低于HS+L组（均P<0.05）。结论 PBMV能在降低高血压小鼠收缩压水平的同时，减轻左心室重塑，其机制可能与PBMV促进淋巴管增生有关。

关键词: 高血压, 心室重构, 血管内皮生长因子受体3, 单核细胞, 淋巴管生成, 流式细胞术, 高盐

Abstract:

Objective To explore the effects of peripheral blood VEGFR-3⁺monocytes (PBMV) on left ventricular (LV) remodeling induced by high salt intake. Methods Six-week-old male C57BL/6 mice were randomly divided into the 0.5% NaCl concentration diet (W/W, normal salt, NS) group, the 8% NaCl concentration diet (W/W, high salt, HS) group, the HS+ N-nitro-L-arginine methyl ester (L-NAME, HS+L) group and the HS+L+PBMV treatment group. PBMV intervention was performed in hypertensive mice from 9-12 weeks after high salt diet intervention. Noninvasive tail pressure was measured by standard tail pressure method in all mice. Cardiac structure and function were determined using a Vevo 2100 ultrasound imaging system. The mRNA levels of tonicity responsive enhancer binding protein (TonEBP) and lymphatic endothelial cell markers in mouse myocardial tissue were detected by fluorescence quantitative PCR. Masson staining was used to observe the degree of myocardial fibrosis. Calculation of cardiomyocyte cross-sectional area (CSA) was analyzed by fluorescence staining of malt germ lectin (WGA). Results At the end of the intervention, the systolic pressure (SBP) was significantly increased in the HS+L group compared with the other groups (P<0.05). The mRNA levels of TonEBP was significantly lower while the lymphatic endothelial cell markers of VEGF-C, Prox-1, Podoplanin and LYVE-1 were significanly higher in the HS+L+PBMV group than those of the HS+L group (P<0.05). Echocardiography measurement demonstrated that the LV end-diastolic dimension (LVEDD) and LV posterior wall thickness (LVPWT) were significantly decreased in the HS+L+PBMV group than those of the HS+L group. The LV ejection fraction (LVEF) and LV fractional shortening (LVFS) were significantly increased in the HS+L+PBMV group compared with those of the HS+L group (P<0.05). The pathological results showed that the CVF and CSA were significantly decreased in the HS+L+PBMV group than those of the HS+L group (P<0.05). Conclusion The present study demonstrates that PBMV treatment can reduce SBP and ameliorate LV remodeling in hypertensive mice, which may be related to promoting lymphangiogenesis.

Key words: hypertension, ventricular remodeling, vascular endothelial growth factor receptor-3, monocytes, lymphangiogenesis, flow cytometry, high salt

中图分类号:

R544.11

图/表 9

参考文献 16

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基因名称	引物序列（5'→3'）	产物大小（bp）
β-actin	上游：CTAAGGCCAACCGTGAAAAG	104
β-actin	下游：ACCAGAGGCATACAGGGACA	104
Prox-1	上游：ATACCGAGCCCTCAACATGC	87
Prox-1	下游：CGTAACGTGATCTGCGCAAC	87
LYVE-1	上游：GGCTTTGAGACTTGCAGCTATG	177
LYVE-1	下游：GCAGGAGTTAACCCAGGTGT	177
Podoplanin	上游：TGGCAAGGCACCTCTGGTA	77
Podoplanin	下游：TGAGGTGGACAGTTCCTCTAAGG	77
VEGF-C	上游：GTTACAGAAGACCGTGTGCGAATC	85
VEGF-C	下游：GATGGGACACAGCGGCATA	85
TonEBP	上游：TTCATAGTTGGAATTTCAGAGCA	153
TonEBP	下游：TTGCGAGTATACAAATGTTCCAA	153

基因名称	引物序列（5'→3'）	产物大小（bp）
β-actin	上游：CTAAGGCCAACCGTGAAAAG	104
β-actin	下游：ACCAGAGGCATACAGGGACA	104
Prox-1	上游：ATACCGAGCCCTCAACATGC	87
Prox-1	下游：CGTAACGTGATCTGCGCAAC	87
LYVE-1	上游：GGCTTTGAGACTTGCAGCTATG	177
LYVE-1	下游：GCAGGAGTTAACCCAGGTGT	177
Podoplanin	上游：TGGCAAGGCACCTCTGGTA	77
Podoplanin	下游：TGAGGTGGACAGTTCCTCTAAGG	77
VEGF-C	上游：GTTACAGAAGACCGTGTGCGAATC	85
VEGF-C	下游：GATGGGACACAGCGGCATA	85
TonEBP	上游：TTCATAGTTGGAATTTCAGAGCA	153
TonEBP	下游：TTGCGAGTATACAAATGTTCCAA	153

组别	基线	8周	12周
NS组	113.13±4.82	115.13±5.69	113.25±4.33
HS组	114.25±4.17	134.63±4.57^a	136.63±13.05^a
HS+L组	112.25±4.23	137.13±6.24^a	152.88±19.36^ab
HS+L+PBVM组	113.63±3.11	138.00±13.71^a	138.50±7.07^ac
F	0.335	13.380^＊＊	12.850^＊＊

组别	基线	8周	12周
NS组	113.13±4.82	115.13±5.69	113.25±4.33
HS组	114.25±4.17	134.63±4.57^a	136.63±13.05^a
HS+L组	112.25±4.23	137.13±6.24^a	152.88±19.36^ab
HS+L+PBVM组	113.63±3.11	138.00±13.71^a	138.50±7.07^ac
F	0.335	13.380^＊＊	12.850^＊＊

组别	TonEBP	VEGF-C	Prox-1	Podoplanin	LYVE-1
NS组	1.00±0.00	1.00±0.00	1.00±0.00	1.00±0.00	1.00±0.00
HS组	2.17±0.27^a	1.88±0.41^a	2.77±0.48^a	2.33±0.64^a	2.69±0.49^a
HS+L组	2.87±0.82^a	1.80±0.40^a	2.56±0.45^a	2.41±0.49^a	2.88±0.55^a
HS+L+PBVM组	2.35±0.72^a	3.16±0.55^abc	3.73±0.34^abc	3.95±0.46^abc	4.38±1.03^abc
F	5.906^＊	15.260^＊＊	28.360^＊＊	20.400^＊＊	14.330^＊＊

VEGFR-3⁺单核细胞对高血压小鼠左心室重塑的影响

Effects of peripheral blood VEGFR-3⁺ monocytes on left ventricular remodeling in mice with hypertension

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组别	第1天	第2天	第3天	第5天	第7天
HS+L组	14.62±0.28	14.92±0.39	14.96±0.31	15.07±0.23	14.89±0.86
HS+L+PBVM组	17.58±1.96	24.67±0.74	27.83±0.98	24.76±3.46	17.26±1.35
t	2.990^＊	23.310^＊＊	25.040^＊＊	5.589^＊＊	2.961^＊

组别	LVEDD（mm）	LVEF	LVFS	LVPWT（mm）
NS组	2.68±0.45	0.65±0.03	0.33±0.03	0.76±0.11
HS组	3.50±0.52^a	0.48±0.04^a	0.24±0.05^a	0.88±0.06^a
HS+L组	4.03±0.15^ab	0.41±0.07^ab	0.19±0.02^ab	0.98±0.11^a
HS+L+PBVM组	3.25±0.06^ac	0.56±0.05^abc	0.27±0.03^ac	0.75±0.08^c
F	12.540^＊＊	21.740^＊＊	17.120^＊＊	6.460^＊＊

组别	CSA（μm²）	CVF（%）
NS组	368.00±41.24	2.23±0.31
HS组	436.50±30.26^a	7.33±1.04^a
HS+L组	592.00±24.12^ab	16.15±2.07^ab
HS+L+PBVM组	498.00±36.89^abc	10.83±1.27^abc
F	31.750^＊＊	77.560^＊＊

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VEGFR-3+单核细胞对高血压小鼠左心室重塑的影响

Effects of peripheral blood VEGFR-3+ monocytes on left ventricular remodeling in mice with hypertension

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VEGFR-3⁺单核细胞对高血压小鼠左心室重塑的影响

Effects of peripheral blood VEGFR-3⁺ monocytes on left ventricular remodeling in mice with hypertension