Dysregulated miR-361-5p/VEGF Axis in the Plasma and Endothelial Progenitor Cells of Patients with Coronary Artery Disease

Abstract

Dysfunction and reduction of circulating endothelial progenitor cell (EPC) is correlated with the onset of cardiovascular disorders including coronary artery disease (CAD). VEGF is a known mitogen for EPC to migrate out of bone marrow to possess angiogenic activities, and the plasma levels of VEGF are inversely correlated to the progression of CAD. Circulating microRNAs (miRNAs) in patient body fluids have recently been considered to hold the potential of being novel disease biomarkers and drug targets. However, how miRNAs and VEGF cooperate to regulate CAD progression is still unclear. Through the small RNA sequencing (smRNA-seq), we deciphered the miRNome patterns of EPCs with different angiogenic activities, hypothesizing that miRNAs targeting VEGF must be more abundant in EPCs with lower angiogenic activities. Candidates of anti-VEGF miRNAs, including miR-361-5p and miR-484, were enriched in not only diseased EPCs but also the plasma of CAD patients. However, we found out only miR-361-5p, but not miR-484, was able to suppress VEGF expression and EPC activities. Reporter assays confirmed the direct binding and repression of miR-361-5p to the 3′-UTR of VEGF mRNA. Knock down of miR-361-5p not only restored VEGF levels and angiogenic activities of diseased EPCs in vitro, but further promoted blood flow recovery in ischemic limbs of mice. Collectively, we discovered a miR-361-5p/VEGF-dependent regulation that could help to develop new therapeutic modalities not only for ischemia-related diseases but also for tumor angiogenesis.

A Dysregulated MicroRNA-26a/EphA2 Axis Impairs Endothelial Progenitor Cell Function via the p38 MAPK/VEGF Pathway

“…In vitro tube formation was assessed as described previously [29]. Briefly, basement membrane extracts were plated in 96-well plates at 37°C to form a reconstituted basement membrane.…”

The regulatory role of microRNAs in angiogenesis‐related diseases

“…Studies showed that miR‐9, miR‐135a, miR‐181a, miR‐181b, miR‐199b and miR‐204 may manage angiogenesis via targeting SIRT1 150. MiR‐200b, miR‐361‐5p, miR‐874, miR‐125‐5p and miR‐146 are involved in angiogenesis by regulating VEGF 151, 152, 153. In addition, the miR‐214/eNOS pathway is involved in Rg1‐induced angiogenesis.…”

Circulating MicroRNAs as Novel Biomarkers of Stenosis Progression in Asymptomatic Carotid Stenosis

“…January 2017 miRNAs had previously been related with processes such as inflammation, [20][21][22] angiogenesis, [23][24][25] or endothelial and vascular smooth muscle cell differentiation, [26][27][28][29][30][31] which invoke major significance at the dysfunctional endothelium leading to atherosclerotic plaque growth, instability, rupture, and subsequent cerebrovascular events.…”

“…Затем плаз-му разделяли на аликвоты в криопробирки Eppendorf и хранили при -80°C. Заболевание периферических артерий 15 (25) Примечание. ВСА -внутренняя сонная артерия.…”

“…При этом мы обнаружили различные профили экспрессии микроРНК в циркулирующих экзосомах у пациентов с прогрессированием БССА по сравнению с пациентами без такового прогрессиро-вания, подтвердив данные результатами ПЦР. Было известно, что все эти миРНК связаны с такими процес-сами, как воспаление [20][21][22], ангиогенез [23][24][25] или дифференцировка эндотелиальных и сосудистых глад-комышечных клеток [26][27][28][29][30][31], которые имеют большое значение в развитии дисфункции эндотелия, ведущей к увеличению размера, нестабильности и разрыву ате-росклеротической бляшки, с последующим развити-ем цереброваскулярных событий [14]. Действительно, миРНК-199b участвует в дифференцировке эндоте-лиальных клеток и ангиогенезе посредством вовле-чения в сигнальный путь фактора роста эндотелия сосудов [23].…”