microRNA‑646 inhibits angiogenesis of endothelial progenitor cells in pre‑eclamptic pregnancy by targeting the VEGF‑A/HIF‑1α axis

Abstract

Pre-eclampsia is a complication that occurs during pregnancy, the pathological feature of which is a change in vascular endothelial homeostasis. microRNA (miR)-646 is an anti-angiogenic miRNA that has been indicated to exhibit potential anti-angiogenic effects in endothelial cells cultured in vitro and in ischemia-induced angiogenesis. However, whether miR-646 has therapeutic potential in placental angiogenesis in pre-eclampsia remains to be determined. In the current study, human peripheral blood-derived endothelial progenitor cells (EPCs) were isolated to study the coordination between miR-646, vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor (HIF)-1α expression in preeclampsia EPCs. EPCs were isolated from human peripheral blood to demonstrate a potential interaction between miR-646 and targets (VEGF-A) in vitro. The number of EPCs and the expression of miR-646 in patients with preeclampsia was detected, and the effects of miR-646 on EPC function and preeclampsia angiogenesis was assessed. Clinical specimens demonstrated that miR-646 expression was enhanced in pregnancy with preeclampsia. The results indicated that miR-646 suppressed EPCs multiplication, differentiation and migration. miR-646 was observed to exert an anti-angiogenic function by suppressing the expression of angiogenic cytokines VEGF-A and HIF-1α. Additionally, luciferase results displayed that miR-646 downregulated VEGF-A expression by directly binding to a specific sequence in its 3'-untranslated region. The results of the current study demonstrated that the miR-646/VEGF-A/HIF-1α axis is significant for angiogenic properties of EPCs in vitro and in vivo placental vasculogenesis. The results of the present study provide a new insight into microRNA regulation of vessel homeostasis and angiogenesis, and a basis for alternative treatments for patients with pre-eclampsia.

Endothelial Colony-Forming Cells Dysfunctions Are Associated with Arterial Hypertension in a Rat Model of Intrauterine Growth Restriction

“…We observed reduced VEGF-A and VEGFR-2 expression in IUGR-ECFCs. Decreased VEGF-A expression has been observed in preeclamptic pregnancy, an obstetric complication often associated with an increased incidence of IUGR [ 71 ], and in the pancreatic islets of IUGR fetal sheep [ 72 ]. In addition, VEGF was markedly downregulated in EPCs isolated from patients with either coronary heart disease [ 73 ] or from diabetic patients, and is associated with decreased eNOS expression [ 74 ].…”

Roles of noncoding RNAs in preeclampsia

“… [ 108 ] miR-133 serum upregulated Rho/ROCK MiR-133 may affect the apoptosis of trophoblasts in the placenta tissues [ 109 ] miR-384 placenta/plasma upregulated PTBP3 Cell proliferation and migration were inhibited by miR-384 overexpression [ 110 ] miR-21 Serum/placenta upregulated FOXM1 MiR-21 may regulate placental cell proliferation [ 111 ] miR-125a-5p placenta/exosome upregulated VEGFA miR-125a-5p might affect HTR8/SVneo cell proliferation and migration and inhibit angiogenesis [ 112 ] miR-214-3p serum upregulated PIGF Downregulation of miR-214-3p promoted trophoblast invasion into the decidua, as well as spiral artery remodeling [ 113 ] miR-518b plasma upregulated EGR1 Increased miR-518b inhibited trophoblast migration and angiogenesis [ 114 ] miRNA-646 serum upregulated VEGF-A miR-646 suppressed endothelial progenitor cells (EPCs) multiplication, differentiation and migration. [ 115 ] miR-215-5p placenta upregulated CDC6 miR-215-5p inhibited both the migration and invasive potential of trophoblasts, besides decreasing the G1-S transition in HTR-8/SVneo cells [ 116 ] miR-483 venous blood/ umbilical cord blood / placental tissue downregulate IGF1 miR-483 regulates the expression of PI3K, Akt, and mTOR in endothelial progenitor cells [ 117 ] …”

Recent Advances of MicroRNAs, Long Non-coding RNAs, and Circular RNAs in Preeclampsia

“…In situ hybridization demonstrated that the level of miR-20a was higher in PE than in normal placental tissue, and showed that the up-regulation of miR-20a can inhibit the proliferation, migration, and invasion of trophoblast cells by inhibiting the expression of forkhead box A1 (FOXA1) . In addition, miR-646 expression is elevated in endothelial progenitor cells isolated from the peripheral blood of pregnant women with PE (Dong D. et al, 2020). miR-646 reduces angiogenesis and inhibits the proliferation, differentiation, and migration of endothelial progenitor cells by down-regulating VEGF-A and HIF-1α expression.…”

“…Enhanced IL-6 expression can reduce miR-223 levels, leading to vascular dysfunction and promoting macrophage infiltration, with adverse effects on the invasion of cytotrophoblast cells into the decidua and myometrium (Lockwood et al, 2008). Immunohistochemistry has further demonstrated that the decidua and trophoblast cells of patients with PE exhibit high expression of IL-6 (Lockwood et al, 2008), which is the main factor inducing decreased miR-223 expression Dong D. et al (2020). Low expression of miR-223 in PE may be a compensatory mechanism that activates endothelial function and increases angiogenesis.…”