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Yang, C.; , .; Hardy, P. MiR-181 in Endothelial Cell Differentiation. Encyclopedia. Available online: https://encyclopedia.pub/entry/23316 (accessed on 13 July 2025).
Yang C,  , Hardy P. MiR-181 in Endothelial Cell Differentiation. Encyclopedia. Available at: https://encyclopedia.pub/entry/23316. Accessed July 13, 2025.
Yang, Chun, , Pierre Hardy. "MiR-181 in Endothelial Cell Differentiation" Encyclopedia, https://encyclopedia.pub/entry/23316 (accessed July 13, 2025).
Yang, C., , ., & Hardy, P. (2022, May 24). MiR-181 in Endothelial Cell Differentiation. In Encyclopedia. https://encyclopedia.pub/entry/23316
Yang, Chun, et al. "MiR-181 in Endothelial Cell Differentiation." Encyclopedia. Web. 24 May, 2022.
MiR-181 in Endothelial Cell Differentiation
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This entry is adapted from the peer-reviewed paper 10.3390/cells11101670

The miR-181 family is one of the essential angiogenic regulators. The miR-181 family consists of four highly conserved members: miR-181a, miR-181b, miR-181c, and miR-181d. They are independently derived from six precursors located on three chromosomes.

miR-181 tumor angiogenesis endothelial dysfunction

1. Introduction

Angiogenesis refers to the formation of new blood vessels from existing vessels and is involved in endothelial cell (EC) proliferation, migration, and morphogenesis. Angiogenesis naturally occurs in an organism during development and physiological processes such as wound healing and the menstrual cycle [1]. It is a dynamic process tightly regulated spatially and temporally among angiogenic factors, extracellular matrix components, and ECs [2]. Angiogenesis is controlled by a precise balance between stimulatory and inhibitory angiogenic factors in healthy tissues [3]. Among the many pro-angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietins (Angs) have emerged as the primary regulators with specificity for ECs. Binding to their receptors on ECs, these factors are responsible for the proliferation, EC migration, and the integrity and maintenance of the vascular network [4]. Fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), hepatocyte growth factor, and matrix metalloproteinases (MMPs) are also known to drive vascular growth [5] Anti-angiogenic factors include angiostatin, endostatin, thrombospondin-1, interferon-γ, anti-factor VIIa, and tissue inhibitors of MMPs (TIMPs). Abnormal angiogenesis occurs when this balance is disturbed and is associated with human pathologies such as cancer, retinopathies, and ischemic diseases [5].
Recent studies revealed that functional non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), circular RNAs (circRNAs), small nucleolar RNAs, and long ncRNAs (lncRNAs) play critical roles in angiogenesis [6]. For example, lncRNAs are a group of more than 200 nt ncRNAs involved in many cellular processes, some of which are dysregulated in pathological angiogenesis. LncRNAs regulate translation by direct binding to target mRNAs, competing endogenous RNAs, and sponging miRNAs [7]. CircRNAs are a class of endogenous ncRNA characterized by their unique structure with a 3′ to 5′ end-joining event [8]. CircRNA expression is cell type- and tissue-specific; they sponge miRNAs to regulate their functions [9]. This review focuses on miRNAs in the context of pathological angiogenesis.
MiRNAs are endogenous, highly conserved, double-stranded, ncRNA molecules of about 20–22 nucleotides in length in their mature form. MiRNAs originally reside in the nucleus and are transcribed by RNA polymerase II into a long primary molecule (pri-miRNA), which is further cleaved into approximately 70–100 nucleotide hairpin-shaped precursors miRNA (pre-miRNA) by RNA-specific RNase III type endonuclease, Drosha, and its cofactor, DiGeorge syndrome critical region (8DGCR8) [10]. The pre-miRNA is actively transported to the cytoplasm via an exportin-5- and ran-GTP-dependent mechanism. Once in the cytoplasm, pre-miRNAs are cleaved into ~22-nt duplex mature miRNA duplexes by dicer, a cytoplasmic double-stranded ribonuclease. Then, the miRNA duplex is integrated into the effector RNA-induced silencing complex (RISC), from which a mature single-stranded miRNA is produced and binds to the 3′-untranslated region (3′-UTR) of target mRNAs to block translation or cleave mRNA. The biogenesis of microRNA was reviewed by Bartel et al. [11]. Many studies suggested the involvement of miRNAs in angiogenesis. Dicer and drosha are necessary for miRNAs expression in ECs and are essential in angiogenesis. Knocking down enzymes reduces capillary development and tubule-forming activity in ECs [12][13]. Many miRNAs exhibit striking organ- or tissue-specific expression patterns; some are found abundantly in angiogenesis-associated ECs and regulate blood vessel development and angiogenesis [14][15][16]. Recently, the roles of miRNAs in tumor angiogenesis have also been extensively investigated [7].

2. MiR-181 Family Members

The miR-181 family consists of four highly conserved members: miR-181a, miR-181b, miR-181c, and miR-181d [17]. They are independently derived from six precursors located on three chromosomes. MiR-181a/b-1 is located on chromosome 1, miR-181a/b-2 is located on chromosome 9, and miR-181c/d clusters on chromosome 19 [18]. Although identical in their mature sequences, miR-181b-1 and miR-181b-2 are located on different chromosomes [19]. No protein-coding regions are found within the chromosomal regions of the miR-181 transcripts, suggesting these miRNAs are transcribed independently. The -3p and -5p strands of each miR-181 family member differ by only a few nucleotides. However, each miR-181 member targets different genes, leading to various functionality and context-sensitive activities [20]. The sequence homology and difference among miR-181a-d, and their gene loci on different chromosomes were elucidated by Indrieri et al. [21]. MiR-181s are aberrantly expressed in tumor tissues and exhibit oncogenic or tumor-suppressive properties in a cancer-specific manner [22][23].

3. MiR-181 in EC Differentiation

The specification of arterial, venous, and lymphatic EC fate is critical during vascular development. Several studies demonstrated the involvement of miR-181 family members in embryonic vascular development and endothelial differentiation. Kazenwadel et al. found higher expression of miR-181a in embryonic blood vascular ECs than lymphatic ECs [24]. The expression of prospero homeobox protein 1 (prox1), a crucial gene for the specification and maintenance of lymphatic EC identity, is directly suppressed by miR-181a. Importantly, increased miR-181a activity in primary embryonic lymphatic ECs resulted in the reprogramming of lymphatic ECs toward a blood vascular phenotype by targeting Prox1, suggesting that miR-181a is critical for the EC fate during vascular development and neo-lymphangiogenesis [24]. Shaik et al. studied the role of miRNAs in the differentiation of adipose-derived stromal/stem cells (ASCs) into the endothelial lineage [25]. They found that miR-181a-5p is upregulated during endothelial differentiation. Although the specific mechanisms of miR-181a-5p function in ASCs are unclear, the overexpression of miR-181a-5p likely induces endothelial differentiation in ASCs [25]. Pluripotent human embryonic stem cells (hESCs) can be directly differentiated toward EC lineages and express a unique panel of miRNAs critical in EC differentiation and developmental angiogenesis [16][26]. Kane et al. investigated the functional role of miRNAs in hESC differentiation to vascular ECs [27]. They observed that miR-181a and miR-181b (miR-181a/b) are increased to a peak in mature hESC-ECs and adult ECs. High levels of miR-181a/b enhanced the expression of EC-specific markers (pecam1 and VE-cadherin) accompanying differentiation of hESCs to vascular ECs. In vivo, overexpression of miR-181b improved hESC-EC-induced therapeutic neovascularization angiogenesis in a mouse model of limb ischemia, indicating that miR-181b is capable of potentiating EC differentiation from pluripotent hESCs and a direct cell effect of transplanted cells may contribution to the in vivo neovascularization.
These data strongly suggest the essential role of miR-181a and miR-181b in embryonic vascular development and inducing embryonic stem cell differentiation toward EC (Table 1). This mechanism suggests a potential strategy for optimizing the generation of pro-angiogenic vascular ECs for regenerative medicine.
Table 1. Roles of miR-181 family members in EC differentiation and EC barrier permeability.
Function MiR-181 Members Upstream Events Target Downstream Signaling/Events Ref
EC differentiation          
promotes lymphangiogenesis toward vascular EC development miR-181a   Prox1 ERK1/2 pathway [24]
induces endotheliogenesis in ASCs miR-181a-5p     VEGF, VWF, CD31 [25]
enhances hESCs differentiation to vascular ECs miR-181a/b     Pecam1, nitric oxide
VE-Cadherin		 [27]
BBB/BTB          
increases BTB permeability miR-181a   KLF6 tight junction proteins [28]
increases BBB permeability miR-181c   PDPK1 cofilin phosphorylation [29]
increases blood-spinal cord barrier (BSCB) permeability miR-181c-5p NHO-1 SOX5 tight junction proteins [30]
increases BTB permeability miR-181d-5p NEAT1 SOX5 tight junction proteins [31]

References

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  18. Ji, J.; Yamashita, T.; Budhu, A.; Forgues, M.; Jia, H.-L.; Li, C.; Deng, C.; Wauthier, E.; Reid, L.M.; Ye, Q.-H.; et al. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 2009, 50, 472–480.
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Subjects: Biochemistry & Molecular Biology
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