Effects of metformin on pregnancy outcome, endocrine and VEGF/MAPK signaling pathway in rats with recurrent spontaneous abortion

doi:10.11958/20221259

Abstract

Abstract:

Objective To investigate effects of metformin (Met) on vascular endothelial growth factor (VEGF)/mitogen-activated protein kinase (MAPK) signaling pathway and ovarian endocrine in recurrent abortion (RSA) rats. Methods Female SD rats were mated with male rats in a ratio of 2∶1, then the female pregnant rats were randomly divided into the control group, the RSA group, the Met low-dose, middle-dose and high-dose groups (250, 1 000, 2 000 mg/kg) and the progesterone group (positive control group, 156 mg/kg), with 10 rats in each group. At 24 hours after the last administration, rats were anesthetized and killed. The embryo loss was observed by dissecting rat uterus. Hematoxylin eosin (HE) staining was used to detect pathological changes of decidual tissue. Radioimmunoassay kit was used to detect serum hormone levels. The protein levels of VEGF/MAPK pathway in uterine decidua were detected by Western blot assay. Results Compared with the control group, the number of dead embryos and the rate of embryo loss were significantly increased in the RSA group, and serum levels of follicle-stimulating hormone (FSH), leuteinizing hormone (LH), pituitary prolactin (PRL), estradiol (E₂), progesterone (P) and protein expressions of VEGF receptor-2 (VEGFR-2), VEGF and phosphorylated extracellular signal-regulated kinase (p-ERK) in decidual tissue were significantly decreased (P<0.05), and the decidual tissue of uterus was seriously damaged. Compared with the RSA group, the number of dead embryos and the rate of embryo loss were significantly decreased in the Met groups. Serum levels of FSH, LH, PRL, E₂, P and the protein expression levels of VEGFR-2, VEGF and p-ERK in decidual tissue were significantly increased (P<0.05). The damage of decidual tissue was alleviated, and high dose of Met showed better control effect on the above indexes. Conclusion Met can alleviate endocrine disorder and uterine decidua damage in RSA rats, which significantly improves the expression of VEGF/MAPK pathway related proteins, and promotes the activation of VEGF/MAPK pathway.

Key words: metformin, abortion, habitual, endothelial growth factors, mitogen-activated protein kinases

CLC Number:

R730.21

Figures/Tables 6

References 21

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组别	存活胚胎数（只）	死亡胚胎数（只）	胚胎丢失率（%）
对照组	56	5	8.19±1.70
RSA组	25	30	54.54±8.29^a
Met低剂量组	31	26	45.61±7.44^b
Met中剂量组	42	19	31.14±7.30^bc
Met高剂量组	49	7	12.50±2.52^bcd
黄体酮组	50	10	16.66±3.36^bcd
F			108.271^＊＊

组别	存活胚胎数（只）	死亡胚胎数（只）	胚胎丢失率（%）
对照组	56	5	8.19±1.70
RSA组	25	30	54.54±8.29^a
Met低剂量组	31	26	45.61±7.44^b
Met中剂量组	42	19	31.14±7.30^bc
Met高剂量组	49	7	12.50±2.52^bcd
黄体酮组	50	10	16.66±3.36^bcd
F			108.271^＊＊

组别		FSH（IU/L）		LH（IU/L）
对照组		7.01±0.27		6.03±0.75
RSA组		5.07±0.11^a		3.09±0.39^a
Met低剂量组		5.71±0.13^b		3.92±0.49^b
Met中剂量组		6.20±0.17^bc		4.86±0.60^bc
Met高剂量组		6.84±0.25^bcd		5.83±0.72^bcd
黄体酮组		6.72±0.24^bcd		5.61±0.70^bcd
F		135.481^＊＊		35.556^＊＊
组别	PRL（mIU/L）		E₂（ng/L）		P（μg/L）
对照组	102.61±5.40		24.20±0.20		2.40±0.21
RSA组	70.06±2.08^a		17.11±0.45^a		1.14±0.10^a
Met低剂量组	78.19±3.01^b		18.71±0.12^b		1.57±0.14^b
Met中剂量组	86.37±3.71^bc		19.94±0.42^bc		1.90±0.17^bc
Met高剂量组	96.37±4.26^bcd		22.46±0.81^bcd		2.28±0.20^bcd
黄体酮组	95.13±4.31^bcd		21.97±0.87^bcd		2.19±0.19^bcd
F	97.383^＊＊		223.454^＊＊		78.160^＊＊

组别		FSH（IU/L）		LH（IU/L）
对照组		7.01±0.27		6.03±0.75
RSA组		5.07±0.11^a		3.09±0.39^a
Met低剂量组		5.71±0.13^b		3.92±0.49^b
Met中剂量组		6.20±0.17^bc		4.86±0.60^bc
Met高剂量组		6.84±0.25^bcd		5.83±0.72^bcd
黄体酮组		6.72±0.24^bcd		5.61±0.70^bcd
F		135.481^＊＊		35.556^＊＊
组别	PRL（mIU/L）		E₂（ng/L）		P（μg/L）
对照组	102.61±5.40		24.20±0.20		2.40±0.21
RSA组	70.06±2.08^a		17.11±0.45^a		1.14±0.10^a
Met低剂量组	78.19±3.01^b		18.71±0.12^b		1.57±0.14^b
Met中剂量组	86.37±3.71^bc		19.94±0.42^bc		1.90±0.17^bc
Met高剂量组	96.37±4.26^bcd		22.46±0.81^bcd		2.28±0.20^bcd
黄体酮组	95.13±4.31^bcd		21.97±0.87^bcd		2.19±0.19^bcd
F	97.383^＊＊		223.454^＊＊		78.160^＊＊

组别	VEGFR-2/GAPDH	VEGF/GAPDH	p-ERK/ERK
对照组	1.16±0.23	1.14±0.22	1.18±0.04
RSA组	0.21±0.08^a	0.15±0.08^a	0.40±0.02^a
Met低剂量组	0.43±0.11^b	0.45±0.10^b	0.58±0.04^b
Met中剂量组	0.71±0.14^bc	0.74±0.15^bc	0.71±0.07^bc
Met高剂量组	0.94±0.18^bcd	0.96±0.19^bcd	1.05±0.09^bcd
黄体酮组	0.91±0.17^bcd	0.93±0.16^bcd	0.97±0.13^bcd
F	49.019^＊＊	54.434^＊＊	161.534^＊＊