Page 15 - Y. Vascular biology

NF-kappaB responsive miR-31-5p elicits endothelial dysfunction associated
with preeclampsia via downregulation of endothelial nitric oxide synthase

Suji Kim
Departments of Molecular and Cellular Biochemistry Kangwon National University School of Medicine

ABSTRACT
Inflammatory cytokines, including TNF-α, were elevated in patients with cardiovascular diseases and are also
considered as crucial factors in the pathogenesis of preeclampsia; however, the underlying pathogenic mechanism
has not been clearly elucidated. The present study provides novel evidence that TNF-α leads to endothelial
dysfunction associated with hypertension and vascular remodeling in preeclampsia through downregulation of eNOS
by NF-kappaB-dependent biogenesis of miR-31-5p, which targets eNOS mRNA. The treatment of human endothelial
cells with TNF-α or miR-31-5p mimic decreased eNOS mRNA stability without affecting eNOS promoter activity,
resulting in inhibition of eNOS expression and NO/cGMP production. Moreover, TNF-α and miR-31-5p mimic evoked
endothelial dysfunction associated with defects in angiogenesis, trophoblastic invasion, and vasorelaxation in an ex
vivo cultured model of human placental arterial vessels, which are typical features of preeclampsia. These results
suggest that NF-kappaB-responsive miR-31-5p elicits endothelial dysfunction, hypertension, and vascular
remodeling via post-transcriptional downregulation of eNOS and is a molecular risk factor in the pathogenesis and
development of preeclampsia.
RESULTS

Figure 1. eNOS mRNA-targeting miR-31-5p is Figure 2. MiR-31-5p levels are elevated in patients with
upregulated in TNF-α-stimulated endothelial cells. preeclampsia and in HUVECs stimulated with TNF-α in a
NF-κB-dependent manner.

Figure 4. MiR-31-5p inhibits angiogenic activity.

Figure 3. MiR-31-5p decreases eNOS expression and
NO/cGMP production.

CONCLUSION

Figure 5. MiR-31-5p impairs relaxation of human
placental arteries.