miR-221 Is Required for Endothelial Tip Cell Behaviors during Vascular Development

Nicoli, Stefania; Knyphausen, Carl-Philipp; Zhu, Lihua Julie; Lakshmanan, Abirami; Lawson, Nathan D.

doi:10.1016/j.devcel.2012.01.008

Cited by 159 publications

(139 citation statements)

References 53 publications

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“…These miRNAs include miR-21, miR-24, miR-34a, miR-92a, miR-126, miR-200b, miR-210, and miR-221/222 cluster ( Figure 2). Many of these miRNAs inhibit angiogenesis by suppressing proliferation and migration of endothelial cells, such as miR-21 by targeting proliferators-activated receptor-alpha (PPAR-α) and RhoB [27]; miR-200b by down-regulating Ets-1, VEGF, VEGFR-2 and GATA2 [28]; miR-92a by suppressing integrin subunit a5 [29]; and miR-221/222 by negatively regulating the expression of c-kit [30]. Moreover, in addition to suppressing angiogenesis by regulating GATA2, miR-24 also induces apoptosis by targeting p21-activating kinase 4 (PAK4) [31].…”

Section: Mirnas Regulate Behaviors Of Vascular Endothelial Cellsmentioning

confidence: 99%

miRNAs and lncRNAs in vascular injury and remodeling

Song

Shan

Chen

et al. 2014

Sci. China Life Sci.

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Vascular injury, remodeling, as well as angiogenesis, are the leading causes of coronary or cerebrovascular disease. The blood vessel functional imbalance trends to induce atherosclerosis, hypertension, and pulmonary arterial hypertension. As several genes have been identified to be dynamically regulated during vascular injury and remodeling, it is becoming widely accepted that several types of non-coding RNA, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are involved in regulating the endothelial cell and vascular smooth muscle cell (VSMC) behaviors. Here, we review the progress of the extant studies on mechanistic, clinical and diagnostic implications of miRNAs and lncRNAs in vascular injury and remodeling, as well as angiogenesis, emphasizing the important roles of miRNAs and lncRNAs in vascular diseases. Furthermore, we introduce the interaction between miRNAs and lncRNAs, and highlight the mechanism through which lncRNAs are regulating the miRNA function. We envisage that continuous in-depth research of non-coding RNAs in vascular disease will have significant implications for the treatment of coronary or cerebrovascular diseases. Vascular network is an intricate series of vessels that act as conduits for blood flow. Their injury and remodeling contribute to atherosclerosis, restenosis after angioplasty, hypertension, and other diseases. Molecular mechanisms that underlie vascular injury and remodeling have been intensively studied during the last two decades [13]. As reported, a number of genes have been shown to regulate vascular remodeling and angiogenesis [47]. As it is increasingly acknowledged that several types of non-coding RNAs are also involved in these processes, they have become a new focus of scientific research [8].According to the recent discoveries in the field of RNA, nearly 60% of transcripts seem to lack protein-coding capacity, termed non-coding RNAs [9]. Bioinformatics observations suggest that non-coding RNAs tend to exist in greater numbers in more sophisticated organisms [10]. Functional studies reveal that non-coding RNAs have essential functions in regulating epigenetic processes, and emerge as important regulators of life activities [11]. Among non-coding RNAs, miRNAs and lncRNAs are particularly interesting and are thus intensively investigated. Here, we provide an overview of the extant research findings pertaining to miRNAs and lncRNAs in vascular functional maintenance, injury, remodeling, and angiogenesis. Moreover, we highlight their implications for the treatment of atherosclerosis, hypertension and other vascular-related disease.

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Section: Mirnas Regulate Behaviors Of Vascular Endothelial Cellsmentioning

confidence: 99%

miRNAs and lncRNAs in vascular injury and remodeling

Song

Shan

Chen

et al. 2014

Sci. China Life Sci.

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“…14,15 Their role in angiogenesis is established. [16][17][18][19] Because the Dll4-Notch signaling pathway is evolutionarily highly conserved, we hypothesized the existence of miRNA families capable of targeting Dll4 and influencing vessel branching. The miR-30 family members are highly conserved between human, mouse, and zebrafish with perfect basepair matching with the 3′untranslated region (UTR) of Dll4 mRNA in these species, suggesting that miR-30 could target and regulate Dll4.…”

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confidence: 99%

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

et al. 2013

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Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension.

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“…To distinguish between genes that encode the same mature miRNA sequence, Postlethwait and collaborators [64] developed the use of digoxigenin-labeled riboprobes designed to bind to miRNA primary transcripts, allowing the observation of miRNA expression for both intergenic and intronic miRNAs. Alternatively to ISH, zebrafish microRNA expression patterns have also been investigated by qPCR, microarray, RNA-seq, and Northern blot analyses at different developmental stages and in different tissues [55,59,65]. As a result, a set of specific miRNAs displays cardiovascularspecific expression patterns, suggesting functional roles in differentiation or homeostasis of these miRNAs during development in zebrafish.…”

Section: Mirna Expression Analysesmentioning

confidence: 99%

“…The Vegf and Notch signaling pathways govern this process. Recently, through deep sequencing and functional screening in zebrafish, a new microRNA has been associated to this process [65]. MiRNA-221 has been found to be essential for angiogenesis since it is required for tip cell proliferation and migration.…”

Section: The Mirna 221mentioning

confidence: 99%

“…miRNAs may speed degradation or slow translation of their targets, but repression caused by either mechanism can be assessed by measuring the protein output of a reporter. The efficiency of ''target protectors'' to block the interaction of miRNAs with a particular binding site in a target mRNA can also be investigated by coinjections with reporter mRNAs containing a GFP/cherry coding sequence and a 3 0 -UTR region with the miRNAbinding site [65,91]. Subsequently, a tested target protector can be used to study whether protection of a specific target mRNA from silencing has any biological effect also in a tissue-specific manner (by generation of a cell autonomous miRNA sensor) [65,67].…”

Section: Target Prediction and Validation Toolsmentioning

confidence: 99%

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The admiR-able advances in cardiovascular biology through the zebrafish model system

Gays

Santoro

2012

Cell. Mol. Life Sci.

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MicroRNAs are small non-coding RNAs endogenously expressed by all tissues during development and adulthood. They regulate gene expression by controlling the stability of targeted messenger RNA. In cardiovascular tissues microRNAs play a role by modulating essential genes involved in heart and blood vessel development and homeostasis. The zebrafish (Danio rerio) system is a recognized vertebrate model system useful to study cardiovascular biology; recently, it has been used to investigate microRNA functions during natural and pathological states. In this review, we will illustrate the advantages of the zebrafish model in the study of microRNAs in heart and vascular cells, providing an update on recent discoveries using the zebrafish to identify new microRNAs and their targeted genes in cardiovascular tissues. Lastly, we will provide evidence that the zebrafish is an optimal model system to undercover new microRNA functions in vertebrates and to improve microRNA-based therapeutic approaches.Keywords MicroRNA Á Zebrafish Á Heart Á Blood vessel Á Development MiRNAs: function and mechanismMicroRNAs (e.g., miRs or miRNAs) are evolutionary conserved small non-coding RNAs, usually 21-25 nt long, that regulate gene expression at a post-transcriptional level.

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miR-221 Is Required for Endothelial Tip Cell Behaviors during Vascular Development

Cited by 159 publications

References 53 publications

miRNAs and lncRNAs in vascular injury and remodeling

miRNAs and lncRNAs in vascular injury and remodeling

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

The admiR-able advances in cardiovascular biology through the zebrafish model system

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