Phenotypic miRNA Screen Identifies miR-26b to Promote the Growth and Survival of Endothelial Cells

Abstract

Endothelial cell (EC) proliferation is a crucial event in physiological and pathological angiogenesis. MicroRNAs (miRNAs) have emerged as important modulators of the angiogenic switch. Here we conducted high-content screening of a human miRNA mimic library to identify novel regulators of EC growth systematically. Several miRNAs were nominated that enhanced or inhibited EC growth. Of these, we focused on miR-26b, which is a conserved candidate and expressed in multiple human EC types. miR-26b overexpression enhanced EC proliferation, migration, and tube formation, while inhibition of miR-26b suppressed the proliferative and angiogenic capacity of ECs. A combinatory functional small interfering RNA (siRNA) screening of 48 predicted gene targets revealed that miR-26b enhanced EC growth and survival through inhibiting PTEN expression. Local administration of miR-26b mimics promoted the growth of new microvessels in the Matrigel plug model. In the mouse model of hindlimb ischemia, miR-26b was found to be downregulated in endothelium in the first week following ischemia, and local overexpression of miR-26b improved the survival of capillaries and muscle fibers in ischemic muscles. Our findings suggest that miR-26b enhances EC proliferation, survival, and angiogenesis. miR-26b is a potential target for developing novel pro-angiogenic therapeutics in ischemic disease.

The Monocyte/High Density Lipoprotein Cholesterol Ratio (MHR) as an Indicator of the Need for Amputation in Patients With Peripheral Artery Disease Developing Critical Limb Ischemia

“…Intense inflammation in the ischemic region has been associated with the contribution of endothelial cells to angiogenesis. 30 In the present study, we found that MHR was an indicator of increased inflammation.…”

MicroRNA-26b-5p Inhibits Mouse Liver Fibrogenesis and Angiogenesis by Targeting PDGF Receptor-Beta

“…The lncMalat1, miR-26b-5p, ULK2 axis regulated brain microvascular endothelial cell autophagy and survival under oxygen-glucose deprivation and reoxygenation condition 36 . A phenotypic miRNA screen identifies that miR-26b-5p can promote endothelial cell growth, survival, and angiogenesis following acute ischemia 37 . In addition, increased miR-26b-5p expression could inhibit the activation of microglia and the production of interleukin-6 in hypoxia-ischemia, thus alleviating the cognitive impairment 38 .…”

“… 36 A phenotypic miRNA screen identifies that miR-26b-5p can promote endothelial cell growth, survival, and angiogenesis following acute ischemia. 37 In addition, increased miR-26b-5p expression could inhibit the activation of microglia and the production of interleukin-6 in hypoxia-ischemia, thus alleviating the cognitive impairment. 38 The miR-26a and/or miR-26b, Cyclooxgenase-2-macrophage inhibitory protein-2 loop regulated a positive feedback between allergic inflammation and tumor metastasis.…”

The relationship between miRNA-26b and connective tissue growth factor in rat models of aortic banding and debanding

“…The relative expression of miRNA-26b was significantly upregulated in the debanding group and not in the banding group. In previous studies, functional annotation analyses of predicted target genes of miRNA-26b have revealed enrichment for genes in FGF, TGFβ, p53, and apoptosis signaling pathways, which are related to cell growth and survival functions [23]. In particular, miRNA-26b is encoded by the introns of its host gene, carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2 (CTDSP2), and reduces the mRNA levels of this host gene [24].…”