Sex-specific alterations in blood-borne factors in physically inactive individuals are detrimental to endothelial cell functions.

Mechanisms underlying the protective effects of both habitual endurance exercise and the female sex on vascular function are incompletely understood. Blood-borne circulating factors, such as circulating microRNAs (ci-miRs), may partially explain these effects. Blood samples were obtained from young, healthy men and women who either habitually performed endurance exercise (endurance trained) or were relatively inactive (sedentary). Women were tested during the early follicular phase of the menstrual cycle or the placebo pill phase of oral contraceptive to control for estrogen. Cultured human umbilical vein endothelial cells (HUVECs) were exposed to participants' serum in migration, proliferation, and reactive oxygen species (ROS) assays. Real-time quantitative polymerase chain reaction was used to quantify an initial array of 84 cardiovascular disease (CVD)-related ci-miRs, followed by validation of 10 ci-miRs. All participants were devoid of traditional CVD risk factors, and circulating estradiol concentration was not different between groups. Serum of endurance-trained women induced greater HUVEC migration compared with serum of sedentary women. HUVEC ROS production was greater in response to serum of sedentary men compared with serum of endurance-trained men and sedentary women. There were sex effects on the levels of nine ci-miRs, with greater levels in men, while ci-miRs-140-5p and 145-5p were also higher in sedentary compared with endurance-trained men and/or women. In a sex-specific manner, habitual endurance exercise was associated with beneficial effects of serum on HUVECs. Thus, alterations in circulating factors may contribute to the protective effects of habitual endurance exercise on vascular health. Additionally, sex had a greater impact than habitual activity level on the levels of vascular-related ci-miRs. Serum from sedentary women caused impaired endothelial migration, whereas serum from sedentary men elicited increased endothelial reactive oxygen species production as compared with serum from their endurance-trained counterparts. Select CVD-related circulating microRNAs (ci-miRs) were higher in men than women, while ci-miRs-140-5p and 145-5p were also higher in sedentary versus trained men and/or women. Our data suggest that alterations in circulating factors may contribute to the protective effects of habitual exercise and sex on vascular health.