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. 2020 Jan 25:2020:1278465.
doi: 10.1155/2020/1278465. eCollection 2020.

Reduced Circulating Endothelial Progenitor Cells and Downregulated GTCPH I Pathway Related to Endothelial Dysfunction in Premenopausal Women with Isolated Impaired Glucose Tolerance

Juan Liu  1 , Xiangbin Xing  2 , Xinlin Wu  3 , Xiang Li  4 , Shun Yao  5 , Zi Ren  6 , Haitao Zeng  6 , Shaohong Wu  7
Affiliations

Reduced Circulating Endothelial Progenitor Cells and Downregulated GTCPH I Pathway Related to Endothelial Dysfunction in Premenopausal Women with Isolated Impaired Glucose Tolerance

Juan Liu et al. Cardiol Res Pract. .

Abstract

Background: Individuals at a prediabetic stage have had an augmented cardiovascular disease (CVD) risk and CVD-related mortality compared to normal glucose tolerance (NGT) individuals, which may be attributed to the impaired vascular endothelial repair capacity. In this study, circulating endothelial progenitor cells' (EPCs) number and activity were evaluated, and the underlying mechanisms in premenopausal women with impaired glucose regulation were explored.

Methods: Circulating EPCs' number and activity and flow-mediated dilation (FMD) were compared in premenopausal women with NGT, isolated impaired fasting glucose (i-IFG), or isolated impaired glucose tolerance (i-IGT). Plasma nitric oxide (NO), EPCs-secreted NO, and intracellular BH4 levels were also measured. The key proteins (Tie2, Akt, eNOS, and GTPCH I) in the guanosine triphosphate cyclohydrolase/tetrahydrobiopterin (GTPCH/BH4) pathway and Tie2/Akt/eNOS signaling pathway were evaluated in these women.

Results: It was observed that the i-IGT premenopausal women not i-IFG premenopausal women had a significant reduction in circulating EPCs' number and activity as well as reduced FMD when compared to NGT subjects. Plasma NO levels or EPCs-secreted NO also decreased only in i-IGT women. The expression of GTCPH I as well as intracellular BH4 levels declined in i-IGT women; however, the alternations of key proteins' expression in the Tie2/Akt/eNOS signaling pathway were not observed in either i-IGT or i-IFG women.

Conclusions: The endothelial repair capacity was impaired in i-IGT premenopausal women but was preserved in i-IFG counterparts. The underlying mechanism may be associated with the downregulated GTCPH I pathway and reduced NO productions.

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Conflict of interest statement

The authors declare they have no conflicts of interest.

Figures

Figure 1
Figure 1
Number and activity of circulating EPCs in the three groups. Circulating EPCs were evaluated by (a) flow cytometric analysis and (b) cell culture assay. The number of circulating EPCs in premenopausal women with i-IGT was significantly lower than that in NGT and i-IFG women (both P < 0.05). No difference of the number of circulating EPCs was observed between NGT and i-IFG women. The migratory (c) and proliferative (d) activities of circulating EPCs in premenopausal women i-IGT were significantly decreased compared to NGT and i-IFG women (all P < 0.05). No difference of the activity of circulating EPCs was observed between NGT and IFG women. Data are given as mean ± SD (∗P < 0.05 vs. NGT; #P < 0.05 vs. IFG, n = 20 for the NGT group and i-IGT group and n = 21 for the IFG group). NGT: normal glucose tolerance; i-IFG: isolated impaired fasting glucose; i-IGT: isolated impaired glucose tolerance; acLDL, acetylated low-density lipoprotein; CD, cluster of differentiation; KDR, kinase-insert domain receptor; EPCs, endothelial progenitor cells.
Figure 2
Figure 2
The NO, VEGF, and GM-CSF levels in plasma and secretion by EPCs in the three groups. Both the plasma NO level (a) and NO secretion by EPCs (d) in premenopausal women with i-IGT was significantly lower than NGT and i-IFG women (all P < 0.05). No difference of NO levels either in plasma or in culture media was observed between NGT and i-IFG women (a and b). No significant difference of VEGF or GM-CSF was found either in plasma level (b and c) or in secretion by EPCs (e and f) between the three groups. Data are given as mean ± SD (∗P < 0.05 vs. NGT; #P < 0.05 vs. IFG, n = 20 for the NGT group and i-IGT group and n = 21 for IFG group). NGT: normal glucose tolerance; i-IFG: isolated impaired fasting glucose; i-IGT: isolated impaired glucose tolerance; GM-CSF, granulocyte macrophage-colony stimulating factor; NGT, normal glucose tolerance; NOx, nitric oxide; VEGF, vascular endothelial growth factor.
Figure 3
Figure 3
The correlations between circulating EPCs or NO production and FMD. The number of circulating EPCs evaluated by flow cytometric analysis (a) or by cell culture (b) strongly correlated with FMD. The migratory (c) or proliferate (d) activity of circulating EPCs also correlated with FMD. Both plasma NO level (e) and NO secretion by EPCs (f) correlated with FMD. LDL, low density lipoprotein; CD, cluster of differentiation; KDR, kinase-insert domain receptor; FMD, flow-mediated brachial artery dilatation; EPCs, endothelial progenitor cells; NO, nitric oxide.
Figure 4
Figure 4
The CTCPH I/BH4 pathway and the Tie2/Akt/eNOS signaling pathway of circulating EPCs in the three groups. Both GTCPH I expression (a) and intracellular BH4 (b) levels were lower in premenopausal women with i-IGT than that in NGT and IFG women (all P < 0.05). No difference of the two indexes was observed between NGT and i-IFG women. Either the phosphorylation forms or the total protein of tie2 (c), Akt (d), and eNOS (e) of circulating EPCs had not exhibited significant difference between each two groups. Data are given as mean ± SD (∗P < 0.05 vs. NGT; #P < 0.05 vs. IFG, n = 20 for the NGT group and i-IGT group and n = 21 for IFG group). NGT: normal glucose tolerance; i-IFG: isolated impaired fasting glucose; i-IGT: isolated impaired glucose tolerance; GTPCH: guanosine triphosphate cyclohydrolase; BH4: tetrahydrobiopterin; Tie2: tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2; Akt: protein kinase B; eNOS: endothelial nitric oxide synthase.
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