血管内皮生长因子及其受体与可溶性血管内皮生长因子受体-1对妊娠期糖尿病与围生儿结局的预测价值

doi:10.3877/cma.j.issn.1673-5250.2013.01.006

目的

探讨妊娠期糖尿病(GDM)孕妇血清中血管内皮生长因子(VEGF)及其受体(VEGFR)所介导的胎盘血管病变与围生儿结局间的关系，以及血清中可溶性血管内皮生长因子受体(sVEGFR)-1水平，对VEGF-VEGFR轴发挥的生物学效应。

方法

选取2011年1月至12月在本中心被诊断为GDM、孕龄为24～28孕周的孕妇100例纳入GDM组；选择同期在相同医院常规产前检查、相同孕龄的50例正常孕妇，纳入对照组。采集两组孕妇血样，测量糖化指标：空腹血糖(FPG)值，糖化血红蛋白(HbA1c)与VEGF。GDM组经常规干预治疗后，再采集血样测定FPG值，HbA1c及VEGF，并与对照组进行统计学分析。分娩后，收集胎盘，分析胎盘组织中VEGFR蛋白表达。根据GDM组孕妇分娩后的围生儿结局，将其分别纳入GDM围生儿异常组(n＝34)与GDM围生儿正常组(n＝66)(本研究遵循的程序符合本院人体试验委员会所制定的伦理学标准，得到该委员会批准，分组征得受试对象本人的知情同意，并与之签署临床研究知情同意书)。

结果

①GDM组孕妇血清VEGF水平、HbA1c及FPG值均明显高于对照组，差异有统计学意义(P<0.05)。②GDM组孕妇经干预治疗后，孕晚期FPG明显降低(P<0.05)，HbA1c与对照组比较，差异无统计学意义(P>0.05)，血清VEGF水平仍保持较高水平。③GDM组孕妇血清VEGF与sVEGFR-1水平呈负相关(r＝－0.497，P<0.01)。④与GDM组孕妇所分娩围生儿的血清VEGF水平显著高于对照组孕妇所分娩围生儿，且差异有统计学意义(P<0.05)。⑤采用多因素非条件logistic回归法对GDM组与对照组孕妇血清VEGF表达水平的分析结果显示，VEGF是GDM围生儿结局异常的危险因子(OR＝5.196, 95% CI: 1.845～14.610，P<0.001)。⑥采用Western印迹法测定胎盘组织中VEGFR蛋白表达量显示，GDM围生儿异常组较GDM围生儿正常组显著升高，差异有统计学意义(P<0.05)。

结论

①GDM孕妇血清VEGF升高是其围生儿结局的一个不利因素，血清VEGF水平高可作为GDM不良围生儿结局的预测指标。②血循环中sVEGFR-1可通过竞争结合方式中和VEGF，抑制其下游信号传递。血清低sVEGFR-1水平可作为GDM病变中VEGF-VEGFR轴过度活跃的生物标记。

关键词: 血管内皮生长因子, 可溶性血管内皮生长因子受体, 妊娠期糖尿病, 胎盘, 围生儿, 预测指标

Objective

To explore the relationship between serum vascular endothelial growth factor (VEGF) and its receptors for VEGF(VEGFR) levels in gestational diabetes mellitus (GDM) women and their perinatal outcomes, and biological effects of serum soluble receptors-1 for VEGF (sVEGFR-1) levels of VEGF-VEGFR axis played.

Methods

From January to December 2011, a total of 100 cases pregnant women diagnosed with GDM between 24-28 weeks gestational age were recruitment in this study as GDM group. Meanwhile recruitment of another 50 cases of normal pregnant women of corresponding gestational age as control group. Extracted blood samples of pregnant women in two groups, measure glycated index: Fasting plasma glucose(FPG), HbA1c, VEGF. After intervention treatment to GDM group, measured FPG, HbA1c, VEGF again and comparison to control group. Collected after delivery of placenta cryopreservation for analysis of tissue expression of VEGFR protein. And collection of maternals and infants clinical information.According perinatals outcome of GDM group, pregnant women were divided into perinatal outcome normal group(n=66) and perinatal outcome abnormal group(n=34). Informed consent was obtained from all participants.

Results

① GDM groups had higher serum VEGF levels, HbA1c and FPG compared with those of control group were much higher, too (P<0.05). ②FPG in GDM group in late pregnancy after intervention treatment. was significantly lower than that in control group(P<0.05). Level of HbA1c in GDM group and in control group had no significance difference (P>0.05). Level of serum VEGF remained high.③In GDM group, maternal serum VEGF and sVEGFR-1 levels were negatively correlated(r=-0.497, P<0.01). ④Serum VEGF level in perinatal outcome abnormal group had significantly higher than that in perinatal outcome normal group (P<0.05). ⑤ Multivariate unconditional logistic regression analysis showed that VEGF was a predictor of adverse perinatal outcome in GDM(OR=5.196, 95% CI: 1.845-14.610, P<0.001). ⑥Determined by Western blotting of VEGFR protein expression in the placenta was also much higher of pregnant women in perinatal outcome abnormal group than that in perinatal outcome normal group (P<0.05).

Conclusions

①High serum VEGF is negative factor for the GDM perinatal outcome. High levels of VEGF can be used as a GDM abnormal perinatal outcome predictor. ②sVEGFR-1 may be in the blood circulation by competitive binding VEGF. Inhibition of downstream signal transduction. Lower serum sVEGFR-1 levels could be as the GDM lesions of VEGF-VEGFR axis overactive biomarkers.

Key words: vascular endothelial growth factor, soluble receptors-1 for VEGF, gestation diabetes mellitus, placenta, perinatal, predictor

表1 两组孕妇血清VEGF，sVEGFR-1，HbA1c及FPG值比较(±s)

Table 1 Comparison of VEGF，sVEGFR-1，HbA1c and FPG between GDM group and control group at 28-32 gestational weeks (±s)

组别	n	FPG(mmol/L)	HbA1c (%)	VEGF(pg/mL)	sVEGFR-1(μg/L)
GDM组	100	6.27±0.88	6.45±1.26	211.17±27.19	16.23±1.57
对照组	50	4.81±0.72	5.68±0.52	94.35±21.18	29.36±2.14
t	?	2.87	2.61	13.34	10.42
P	?	<0.05	<0.05	<0.01	<0.01

表1 两组孕妇血清VEGF，sVEGFR-1，HbA1c及FPG值比较(±s)

Table 1 Comparison of VEGF，sVEGFR-1，HbA1c and FPG between GDM group and control group at 28-32 gestational weeks (±s)

组别	n	FPG(mmol/L)	HbA1c (%)	VEGF(pg/mL)	sVEGFR-1(μg/L)
GDM组	100	6.27±0.88	6.45±1.26	211.17±27.19	16.23±1.57
对照组	50	4.81±0.72	5.68±0.52	94.35±21.18	29.36±2.14
t	?	2.87	2.61	13.34	10.42
P	?	<0.05	<0.05	<0.01	<0.01

表2 GDM组孕妇经干预治疗后，血清VEGF，sVEGFR-1，HbA1c及FPG值与对照组比较(±s)

Table 2 Comparison of VEGF，sVEGFR-1，HbA1c and FPG between GDM group after treatment and control group(±s)

组别	n	FPG(mmol/L)	HbA1c (%)	VEGF(pg/mL)	sVEGFR-1(μg/L)
GDM组	100	5.69±0.74	5.71±0.92	204.27±28.38	18.56±1.61
对照组	50	4.70±0.69	5.47±0.53	91.50±20.42	28.15±1.95
t	?	1.76	1.85	12.84	9.13
P	?	>0.05	>0.05	<0.01	<0.01

表2 GDM组孕妇经干预治疗后，血清VEGF，sVEGFR-1，HbA1c及FPG值与对照组比较(±s)

Table 2 Comparison of VEGF，sVEGFR-1，HbA1c and FPG between GDM group after treatment and control group(±s)

组别	n	FPG(mmol/L)	HbA1c (%)	VEGF(pg/mL)	sVEGFR-1(μg/L)
GDM组	100	5.69±0.74	5.71±0.92	204.27±28.38	18.56±1.61
对照组	50	4.70±0.69	5.47±0.53	91.50±20.42	28.15±1.95
t	?	1.76	1.85	12.84	9.13
P	?	>0.05	>0.05	<0.01	<0.01

图1 胎盘组织中VEGFR蛋白的表达结果(1：对照组；2：GDM围生儿正常组；3：GDM围生儿异常组)

Figure 1 The expression of VEGFR protein in placental tissue(1: Control group; 2：Normal perinatal child of GDM; 3：Abnormal perinatal child of GDM)

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Study of the Relationship Between Vascular Endothelial Growth Factor and Perinatal Outcome of Gestational Diabetes Mellitus

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Study of the Relationship Between Vascular Endothelial Growth Factor and Perinatal Outcome of Gestational Diabetes Mellitus