The Effect of Sex Differences on Endothelial Function and Circulating Endothelial Progenitor Cells in Hypertriglyceridemia

Abstract

Background: Men have a higher risk and earlier onset of cardiovascular diseases compared with premenopausal women. Hypertriglyceridemia is an independent risk factor for the occurrence of ischemic heart disease. Endothelial dysfunction is related to the development of ischemic heart disease. Whether sex differences will affect the circulating endothelial progenitor cells (EPCs) and endothelial function in hypertriglyceridemia patients or not is not clear.

Methods: Forty premenopausal women and forty age- and body mass index (BMI)-matched men without cardiovascular and metabolic disease were recruited and then divided into four groups: normotriglyceridemic women (women with serum triglycerides level <150 mg/dl), hypertriglyceridemic women (women with serum triglycerides level ≥150 mg/dl), normotriglyceridemic men (men with serum triglycerides level <150 mg/dl), and hypertriglyceridemic men (men with serum triglycerides level ≥150 mg/dl). Peripheral blood was obtained and evaluated. Flow-mediated dilatation (FMD), the number and activity of circulating EPCs, and the levels of nitric oxide (NO), vascular endothelial growth factor (VEGF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in plasma and culture medium were measured.

Results: The number and activity of circulating EPCs, as well as the level of NO in plasma or culture medium, were remarkably increased in premenopausal females compared with those in males both in the hypertriglyceridemic group and the normotriglyceridemic group. The EPC counts and activity, as well as the production of NO, were restored in hypertriglyceridemic premenopausal women compared with those in normal women. However, in hypertriglyceridemic men, the EPC counts and activity, as well as levels of NO, were significantly reduced. The values of VEGF and GM-CSF were without statistical change.

Conclusions: The present study firstly demonstrated that there were sex differences in the number and activity of circulating EPCs in hyperglyceridemia patients. Hypertriglyceridemic premenopausal women displayed restored endothelial functions, with elevated NO production, probably mediated by estradiol. We provided a new insight to explore the clinical biomarkers and therapeutic strategies for hypertriglyceridemia-related vascular damage.

Figure 1

(a) fluorescence-activated cell sorting analysis. (b) Phase-contrast fluorescent microscope. There was no significant difference in the level of circulating EPCs between the normotriglyceridemic and the hypertriglyceridemic women. In both the normotriglyceridemic and hypertriglyceridemic patients, the number of EPCs in women groups was statically higher than that in the men groups. Data were presented as mean ans standard deviation. #vs premenopausal women.

Figure 2

(a) The migratory and (b) the proliferative activities of EPCs were statically elevated in the female groups (both normotriglyceridemic and hypertriglyceridemic) than those in the male groups. The migratory and the proliferative activities of EPCs were lower in the hypertriglyceridemic men group than those in the normotriglyceridemic men group. However, the migratory and the proliferative activities of EPCs in normotriglyceridemic premenopausal women were similar to those in hypertriglyceridemic premenopausal women. Data were presented as mean and standard deviation. ☆vs. normotriglyceridemic. #vs premenopausal women.

Figure 3

The plasma levels of NO, VEGF, and GM-CSF. (a) The plasma levels of NO in normotriglyceridemic and hypertriglyceridemic men were statically lower than those in the female groups (P < 0.05). In the male groups, the level of NO was decreased in hypertriglyceridemic subjects than that in normotriglyceridemic subjects (P < 0.05). The plasma levels of NO between normotriglyceridemic and hypertriglyceridemic premenopausal female groups displayed no significant difference (P > 0.05). (b) and (c) The plasma level of VEGF and GM-CSF had no statistical difference between the four groups.

Figure 4

The levels of NO, VEGF, and GM-CSF secreted by cultured EPCs. (a) The level of NO produced by cultured EPCs of the normotriglyceridemic and hypertriglyceridemic men groups was remarkably lower than that of the premenopausal women groups. Besides, the secretion of NO from hypertriglyceridemic men was statically elevated compared with that from normotriglyceridemic men. Nevertheless, the level of NO in the EPCs cultural media of the hypertriglyceridemic premenopausal women was not significantly different from that of the normotriglyceridemic premenopausal women). (b) and (c) There was no obvious difference in VEGF or GM-CSF secretion between four groups.

Figure 5

The correlation between FMD and EPCs or NO level. (a) and (b) There was a positive relevance between FMD and the proliferative or migratory activity of circulating ECPs. Besides, (c) and (d) FMD was positively correlated with the plasma NO level or NO level detected from cultured media.