A brief primer on microRNAs and their roles in angiogenesis
© Anand; licensee BioMed Central Ltd. 2013
Received: 15 November 2012
Accepted: 11 January 2013
Published: 16 January 2013
Development of the vasculature is a complex, dynamic process orchestrated by a balance of pro and anti-angiogenic signaling pathways. The same signaling pathways are mis-regulated and exploited during pathological angiogenesis in cancer, inflammation and cardiovascular diseases and contribute to disease progression. In the last decade, small non-coding RNA molecules termed microRNAs (miRs) have emerged as key regulators of several cellular processes including angiogenesis. It is becoming clear that miRs function in complex networks and regulate gene expression both at the mRNA and protein levels thereby altering cellular signaling responses to specific stimuli. In the vasculature, miRs can function either in a pro-angiogenic manner and potentiate angiogenesis or act as anti-angiogenic miRs by enhancing cell death and decreasing endothelial proliferation. This review aims to provide an update on how microRNAs regulate gene expression and illustrate miR function in the vasculature with a discussion of potential applications of miRs as anti-angiogenic therapeutics.
KeywordsAngiogenesis microRNA networks miR-126 miR-132 p120RasGAP NOTCH Ocular angiogenesis
Vascular endothelium is a highly complex organ with a growing list of sophisticated functions. Endothelial cells have been implicated in diverse functions ranging from release of cytokines during influenza infections , maintenance of hematopoietic stem cells , to adipogenesis of both white and brown fat cells . Suffice to say that endothelial cells have moved beyond the label of ‘cells lining the blood vessels’. Given such a broad array of functions, it is not surprising that there are multiple signaling networks  with several checks and balances that control endothelial responses to external perturbations. Over the last few years, microRNAs have emerged as critical regulators of signaling pathways in multiple cell types including endothelial and perivascular cells. There are several excellent reviews that have summarized the different miRs involved in vascular function during development and disease [5–7]. Here, I will focus on providing a broad framework to understand miR function and illustrate features of specific miRs in the regulation of angiogenesis.
How are microRNAs made?
MicroRNAs (miRs) are small 20-24 nucleotide long RNAs that regulate gene expression by binding to mRNAs. miRs represent about 1-2% of the genes in several species including mammals . Current version of miRbase reports 1600 precursors and 2042 mature miR sequences for humans and 855 precursors and 1281 mature miRs for mice . It is estimated that miRs could well regulate 30-50% of protein coding genes. A large portion of miRs is encoded in introns of genes or in intergenic regions. They are transcribed as a primary miR (pri-miRNA) transcript by RNA polymerase II in conjunction with specific transcription factors that bind to a region upstream similar to a protein coding gene. These miR transcripts are then cleaved by a heterodimer of dsRNA binding proteins, Drosha and DiGeorge Syndrome Critical Region 8 (DGCR8), releasing a 55-70 nt small RNA hairpin termed pre-miR. This RNA hairpin is then exported out of the nucleus by Exportin-5 and Ran-GTP. In the cytoplasm, another RNAse III enzyme, Dicer cleaves the pre-miRs to generate 22nt duplex RNAs. These are now mature miRs that get incorporated into RNA induced silencing complex (termed RISC) consisting of two major classes of proteins Argonaute and GW182. While this is the canonical pathway of miR biogenesis, recent research has shown several alternative pathways depending on cell type, organism and biological contexts [10, 11]. For example, the loss of Dicer leads to a more significant phenotype in the brain and embryonic stem cells compared to the loss of either Drosha or DGCR8. Similarly, loss of Dicer in the vasculature has a more profound effect than the loss of Drosha suggesting there may be Drosha independent mechanisms of miR biogenesis . These observations highlight the degree of complexity in the different RNA processing pathways.
How do miRs work?
When miRs were initially described, it was proposed that miRs bind to target mRNAs using a seed sequence consisting of 6-8 continuous bases and a few more complementary bases along the miR sequence. In plants, miRs have almost perfect complementarity with the target mRNA and these targets undergo direct RNAse mediated cleavage . However, the mammalian miRs rarely had perfect complementarity with their targets. Therefore, it was hypothesized that mammalian miRs suppressed translation of target mRNAs leading to a decrease in target proteins . Interestingly, recent work based on mRNA arrays and ribosome profiling has shown that miRs can also cause mRNA decay in mammalian cells and this is likely due to deadenylation of the mRNA . The relative contributions of mRNA decay and translation inhibition mechanisms in suppressing the target protein levels remains an area of active investigation .
What do miRs do that proteins cannot do?
It has been postulated that miRs maintain robustness of gene expression by insulating biological systems against noise . For example, miR-1 and miR-7 in Drosophila insulate muscle differentiation and photoreceptor determination from external perturbations [18, 19]. While there are other regulatory mechanisms that control gene expression programs such as transcriptional regulators, epigenetic modifications etc, miRs offer a unique advantage by regulating gene expression in the cytoplasm. Moreover, there are miRs that could be upregulated rapidly in cells up to several thousand copies per cell thereby achieving greater potency than otherwise possible. There have been simulations that demonstrate that miR mediated feed forward loops are more effective than transcriptional repressors in buffering gene expression against external perturbations . Finally, the fact that miRs can regulate multiple targets, often several of them in a single pathway, makes them a more effective tool to modulate gene expression in response to specific stimuli.
Are miRs essential in the vasculature?
The importance of miRs in vascular development was apparent based on loss-of-function studies of Dicer. Dicer hypomorphic mice had severe vascular deformation in both the embryo and the yolk sac and died at E12.5-E-14.5 . Similarly, loss of Dicer led to pericardial edema and impaired circulation in zebrafish embryos . Moreover, endothelial specific deletion of Dicer in mice decreased postnatal angiogenesis in response to multiple stimuli . Similarly, inducible deletion of Dicer in vascular smooth muscle cells in mice led to impaired contractility, smooth muscle differentiation and vascular remodeling . Taken together, these early studies established that the loss of Dicer and the concomitant loss of miR processing activity caused significant structural and functional defects in the vascular compartment.
Which miRs regulate vascular function?
The first study to report a putative role for specific microRNAs in endothelial cells was performed by Poliseno et al. The authors used microarray based profiling and identified the most abundant miRs in HUVECs . They reported that several miRs were predicted to target angiogenic growth factor receptors and characterized miR-221/222 as negative regulators of angiogenesis. One of the earliest miRs reported to affect endothelial function in vivo was miR-126. miR-126 is the most abundant microRNA in endothelial cells. Loss-of-function studies in mice and Zebrafish highlighted that miR-126 is important for developmental and pathological angiogenesis and implicated Sprouty Related EVH Domain containing protein 1(SPRED1), a negative regulator of Vascular Endothelial Growth Factor (VEGF) signaling, as a critical target of miR-126 [26, 27]. Interestingly, experiments in Zebrafish demonstrate that blood flow can upregulate miR-126 via activation of Klf2, a mechanosensitive transcription factor . Png and colleagues reported recently that miR-126 regulates endothelial cell recruitment to metastatic breast cancer cells, in vitro and in vivo. They showed that miR-126 downregulated a complex network of targets IGFBP2, PITPNC1a and MERTK and suppressed metastatic endothelial recruitment, metastatic angiogenesis and metastatic colonization. These experiments suggest that the non-endothelial miR-126 can still impact angiogenesis albeit in an anti-angiogenic manner.
While the majority of miRs that have been reported function as pro-angiogenic miRs, miR-17 ~ 92 cluster, a well-characterized group of miRs plays a critical role as a negative regulator of angiogenesis [30, 31]. Bonauer et al showed that miR-92a has an anti-angiogenic effect partly through targeting the integrin subunit α5. Loss of miR-92a improved functional recovery after myocardial infarction and limb ischemia by enhancing blood vessel growth [30, 31].
Summary of different miRs and their roles in vascular cells
Increases EC proliferation, migration
Enhances VEGF signaling in ECs
SPRED1, PIK3R2, VCAM-1
Enhances growth factor signaling
Stimulates tube formation and migration
Inhibits cell proliferation, Anti-angiogenic
Inhibits growth factor receptor recycling and degradation
Hepatocyte-growth factor regulated tyrosine kinase substrate
Stablizes HIF-1, proangiogenic
Anti-angiogenic. Inhibition enhanced neovascularization in ischemic tissues
Critical for VSMC differentiation
Increases VSMC proliferation
miR-132 in endothelial and perivascular cells
We identified miR-132 as an angiogenic miR that functions by regulating p120RasGAP and Ras signaling pathways using a human embryonic stem cell vasculogenesis model and primary endothelial cells . We demonstrated that reciprocal expression of miR-132 and its target p120RasGAP correlated with pathological angiogenesis in human breast tumors and in human hemangiomas. Targeted delivery of an anti-miR-132 decreased angiogenesis and tumor progression in mouse tumor xenograft models. Consistent with our observations in vascular endothelial cells, Lagos et al reported that miR-132 is upregulated with similar kinetics and plays a key role in lymphatic endothelial cells during viral infections . More recently, Mulik et al showed that miR-132 expression was upregulated by a VEGF-A and IL-17 dependent mechanism after ocular infection with Herpes Simplex Virus (HSV) . The authors demonstrated that in vivo silencing of miR-132 by the provision of anti-miR-132 nanoparticles to HSV-infected mice led to reduced corneal neovascularization and diminished lesions. Taken together, these observations indicate that miR-132 may play an important role in pathological neovascularization downstream of multiple triggers including tumor-derived growth factors, viral infections and inflammation.
Subsequent to our work, other groups have reported the function of miR-132 in perivascular cells. Natarajan and colleagues showed time- and dose-dependent up-regulation of miR-132/212 by Ang II through the Ang II Type 1 receptor . They identified phosphatase and tensin homolog (PTEN) as a novel target of miR-132 and demonstrated that miR-132 induces monocyte chemoattractant protein-1 in rat VSMC. The authors demonstrated the presence of a positive feedback loop where phosphorylation of cAMP Response Element Binding protein (CREB) led to miR-132 transcription; miR-132 overexpression resulted in enhanced CREB phosphorylation via p120RasGAP downregulation. In addition, the authors observed that aortas from Ang II-infused mice displayed similar up-regulation of miR-132/212 and monocyte chemoattractant protein-1 and concluded that miR132/212 can serve as a novel cellular node to fine-tune and amplify Ang II actions in VSMC.
Another recent study  showed that miR-132 was constitutively expressed and secreted by saphenous vein pericytes and facilitates cardiac regeneration following myocardial infarction. Both CREB and miR-132 were activated by treatment of these cells by VEGF-B or hypoxia/starvation. The authors report that miR-132 is secreted by these pericytes and can act as a paracrine activator of cardiac healing, highlighting a non-cell autonomous role for miR-132.
What triggers miR expression?
The vasculature is exposed to several stimuli and stressors during developmental and pathological angiogenesis that trigger distinct miR expression profiles. For instance, miR-210 and miR-424 have been shown to be upregulated in response to hypoxia [38, 41]. We have observed specific miRs upregulated in response to angiogenic growth factors VEGF and bFGF . Other studies have also documented miRs regulated by Notch pathway signaling  and cytokines such as IL-3 . These stimuli subsequently trigger miR expression via classic signal transduction pathways and transcription factors. For example, miR-132 is transcribed by CREB in multiple cell types including endothelial cells, vascular smooth muscle cells and neurons [36, 37, 49]. Harris et al have shown that miR-126 is transcribed by Ets family members Ets-1 and Ets-2 . Interestingly, Nicoli et al demonstrated that blood flow induced mechanosensitive transcription factor Klf2a can also transcribe miR-126 during aortic arch development in Zebrafish . While the factors that induce miR expression have been widely characterized, regulatory sequences such as promoters for specific miRs have not yet been well defined and remain an area of considerable interest.
How do miR-target networks regulate angiogenic signals?
While initial reports of miR function focused on one or two specific targets of miRs, it is becoming clear that the biology of miR-target interaction is much more complicated than simple RNA-RNA binding that is the basis of target prediction algorithms. Recent evidence suggests that evolution of conserved miR/target networks can exert powerful influence on biological functions . Given these considerations, one can envision future work in understanding physiological roles of miRs will include systems level analysis of multiple miRs and targets.
Are miRs ‘druggable’ targets in human diseases?
Different strategies to inhibit miR function in vivo
Cholesterol conjugated 2’-O-Methyl antisense oligonucleotides
Locked nucleic acid based antisense oligos
Oligos with multiple miR binding sites to act as competitive inhibitors
Oligos with gene specific sequences complementary to miR binding sites
Targeting anti-miR therapeutics to specific tissues. Naked injection of anti-miRs or cholesterol conjugated antagomiRs typically results in excellent delivery to the liver. However, targeting specific anti-miRs to tissues such as tumor vasculature or sites of ischemic injury is still challenging. Nanoparticles and other delivery vehicles with targeting peptides may be useful in delivering anti-miRs for specific applications .
The delivery of double stranded miR/miR mimics to tumor cells is still challenging and faces similar roadblocks as siRNA therapies. Recent work that shows that a single guide strand of RNA is sufficient to mediate RNA interference is exciting. This could lead to more efficient delivery of miRs to tumor cells in vivo [57, 58].
The mechanism of action of miRs/anti-miRs is complicated by the number of potential targets that could be affected by a miR. There are discrepancies between prediction algorithms and experimental observations, not to mention cell type specific effects and differences in targets between human and mouse. Therefore, global analysis of mRNA and protein levels in cells/tissues that are targeted by the miR therapeutics may be warranted to understand the mechanism(s) of action.
miR inhibitors as anti-angiogenic agents in ocular disease
miR inhibitors can be effective as simple oligonucleotides in ocular disease without the above mentioned requirements for specific delivery systems. Anti-angiogenic therapy, most notably, anti-VEGF antibody has shown significant therapeutic benefit in patients with Age-related Macular Degeneration (AMD) and consequently garnered several accolades including ‘Science-Breakthrough of the year 2006’ and the 2010 Lasker award . There is proof-of-principle that targeting the VEGF pathway in the eye using single-strand RNA-based therapies can effectively block pathological neovascularization in humans, such as the VEGF RNA-aptamer Macugen/pegaptanib, which is approved for macular degeneration . While the success of anti-VEGF approaches have been remarkable, it is not clear whether there are any long-term effects of targeting VEGF. Recently, Kurihara, Westenskow et al show that conditional deletion of Vegfa in adult mouse retinal pigmented epithelial (RPE) cells leads to vision loss and ablation of the choriocapillaris, the major blood supply for the outer retina and photoreceptor cells . It appears that the loss of VEGF resulted in the downregulation of multiple angiogenic genes relevant for physiological and pathological angiogenesis. Therefore the authors conclude that endogenous VEGF provides trophic support necessary for retinal function.
Interestingly, our work has identified several promising miRs that are downstream of VEGF signaling pathways that can be pursued as alternatives to VEGF inhibitors in the eye. We demonstrated that anti-miR-132 is able to decrease developmental angiogenesis in neonatal retinas without affecting established vasculature . Since the intraocular injection of anti-miR reagents selectively interferes with angiogenic endothelial cells that have upregulated miR-132 and not the normal quiescent vasculature, it is likely that this strategy will not have the global effects observed with VEGF ablation. In collaboration with Friedlander and colleagues, we have now observed that anti-miR-132 is a potent inhibitor of pathological neovascularization in the eye in various mouse models (Westenskow and Friedlander, submitted). It remains to be seen if long term use of anti-miR-132 and more broadly anti-angiogenic miRs, can circumvent some of the adverse effects associated with the lack of VEGF in the eye while effectively inhibiting pathological neovascularization.
The emergence of miRs as regulators of gene expression has undoubtedly altered our understanding of how diverse stimuli affect function in the vasculature. miRs have been shown to alter specific signaling pathways that affect proliferation, differentiation, migration and cell survival in endothelial cells and smooth muscle cells. The challenges moving forward would be to integrate the different miRs and their target networks in the stimulus–response cycles of the vasculature and to understand how manipulating one or more miRs can alter cell function in vitro and in vivo. The therapeutic potential of these molecules as anti-angiogenic agents has been shown in multiple animal models and we may be just a few years away from using them to target aberrant angiogenesis in humans.
S.A. is supported by a K99/R00 Pathway to Independence Award (HL112962) from NHLBI. I wish to acknowledge David Cheresh and members of the Cheresh Laboratory for useful discussions.
- Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F, Martinborough E, Peach R, Oldstone MB, Rosen H: Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell. 2011, 146 (6): 980-991.PubMed CentralView ArticlePubMedGoogle Scholar
- Ding L, Saunders TL, Enikolopov G, Morrison SJ: Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012, 481 (7382): 457-462.PubMed CentralView ArticlePubMedGoogle Scholar
- Tran K-V, Gealekman O, Frontini A, Zingaretti Maria C, Morroni M, Giordano A, Smorlesi A, Perugini J, De Matteis R, Sbarbati A, et al: The vascular endothelium of the adipose tissue gives rise to both white and brown Fat cells. Cell Metabol. 2012, 15 (2): 222-229.View ArticleGoogle Scholar
- Chung AS, Ferrara N: Developmental and pathological angiogenesis. Annual Rev Cell Develop Biol. 2011, 27 (1): 563-584.View ArticleGoogle Scholar
- Bonauer A, Boon RA, Dimmeler S: Vascular microRNAs. Curr Drug Targets. 2010, 11 (8): 943-949.View ArticlePubMedGoogle Scholar
- Hartmann D, Thum T: MicroRNAs and vascular (dys)function. Vasc Pharmacol. 2011, 55 (4): 92-105.View ArticleGoogle Scholar
- Small EM, Olson EN: Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011, 469 (7330): 336-342.PubMed CentralView ArticlePubMedGoogle Scholar
- Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 2009, 136 (2): 215-233.PubMed CentralView ArticlePubMedGoogle Scholar
- Kozomara A, Griffiths-Jones S: miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 2011, 39 (suppl 1): D152-D157.PubMed CentralView ArticlePubMedGoogle Scholar
- Treiber T, Treiber N, Meister G: Regulation of microRNA biogenesis and function. Thromb Haemost. 2012, 107 (4): 605-610.View ArticlePubMedGoogle Scholar
- Yang J-S, Lai Eric C: Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Molecular cell. 2011, 43 (6): 892-903.PubMed CentralView ArticlePubMedGoogle Scholar
- Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S: Role of dicer and drosha for endothelial microRNA expression and angiogenesis. Circ Res. 2007, 101 (1): 59-68.View ArticlePubMedGoogle Scholar
- Zhang B, Pan X, Cobb GP, Anderson TA: Plant microRNA: a small regulatory molecule with big impact. Dev Biol. 2006, 289 (1): 3-16.View ArticlePubMedGoogle Scholar
- Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP: The impact of microRNAs on protein output. Nature. 2008, 455 (7209): 64-71.PubMed CentralView ArticlePubMedGoogle Scholar
- Guo H, Ingolia NT, Weissman JS, Bartel DP: Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010, 466 (7308): 835-840.PubMed CentralView ArticlePubMedGoogle Scholar
- Huntzinger E, Izaurralde E: Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet. 2011, 12 (2): 99-110.View ArticlePubMedGoogle Scholar
- Ebert Margaret S, Sharp Phillip A: Roles for MicroRNAs in conferring robustness to biological processes. Cell. 2012, 149 (3): 515-524.PubMed CentralView ArticlePubMedGoogle Scholar
- Li X, Cassidy JJ, Reinke CA, Fischboeck S, Carthew RW: A microRNA imparts robustness against environmental fluctuation during development. Cell. 2009, 137 (2): 273-282.PubMed CentralView ArticlePubMedGoogle Scholar
- Sokol NS, Ambros V: Mesodermally expressed drosophila microRNA-1 is regulated by twist and is required in muscles during larval growth. Genes Dev. 2005, 19 (19): 2343-2354.PubMed CentralView ArticlePubMedGoogle Scholar
- Osella M, Bosia C, Corá D, Caselle M: The role of incoherent MicroRNA-mediated feedforward loops in noise buffering. PLoS Comput Biol. 2011, 7 (3): e1001101-PubMed CentralView ArticlePubMedGoogle Scholar
- Yang WJ, Yang DD, Na S, Sandusky GE, Zhang Q, Zhao G: Dicer is required for embryonic angiogenesis during mouse development. J Biol Chem. 2005, 280 (10): 9330-9335.View ArticlePubMedGoogle Scholar
- Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP, Schier AF: MicroRNAs regulate brain morphogenesis in zebrafish. Science. 2005, 308 (5723): 833-838.View ArticlePubMedGoogle Scholar
- Suarez Y, Fernandez-Hernando C, Yu J, Gerber SA, Harrison KD, Pober JS, Iruela-Arispe ML, Merkenschlager M, Sessa WC: Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci U S A. 2008, 105 (37): 14082-14087.PubMed CentralView ArticlePubMedGoogle Scholar
- Albinsson S, Skoura A, Yu J, DiLorenzo A, Fernandez-Hernando C, Offermanns S, Miano JM, Sessa WC: Smooth muscle miRNAs are critical for post-natal regulation of blood pressure and vascular function. PLoS One. 2011, 6 (4): e18869-PubMed CentralView ArticlePubMedGoogle Scholar
- Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G: MicroRNAs modulate the angiogenic properties of HUVECs. Blood. 2006, 108 (9): 3068-3071.View ArticlePubMedGoogle Scholar
- Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DY, Srivastava D: miR-126 regulates angiogenic signaling and vascular integrity. Develop cell. 2008, 15 (2): 272-284.View ArticleGoogle Scholar
- Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN: The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Develop cell. 2008, 15 (2): 261-271.View ArticleGoogle Scholar
- Nicoli S, Standley C, Walker P, Hurlstone A, Fogarty KE, Lawson ND: MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature. 2010, 464 (7292): 1196-1200.PubMed CentralView ArticlePubMedGoogle Scholar
- Png KJ, Halberg N, Yoshida M, Tavazoie SF: A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature. 2012, 481 (7380): 190-194.View ArticleGoogle Scholar
- Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, et al: MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science. 2009, 324 (5935): 1710-1713.View ArticlePubMedGoogle Scholar
- Doebele C, Bonauer A, Fischer A, Scholz A, Reiss Y, Urbich C, Hofmann W-K, Zeiher AM, Dimmeler S: Members of the microRNA-17-92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells. Blood. 2010, 115 (23): 4944-4950.View ArticlePubMedGoogle Scholar
- Anand S, Cheresh DA: Emerging role of micro-RNAs in the regulation of angiogenesis. Genes & cancer. 2011, 2 (12): 1134-1138.View ArticleGoogle Scholar
- Landskroner-Eiger S, Moneke I, Sessa WC: MiRNAs as modulators of angiogenesis. Cold Spring Harbor perspect med. 2012, 10.1101/cshperspect.a006643. Advance Online PublicationGoogle Scholar
- Otsuka M, Zheng M, Hayashi M, Lee JD, Yoshino O, Lin S, Han J: Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. J Clin Invest. 2008, 118 (5): 1944-1954.PubMed CentralView ArticlePubMedGoogle Scholar
- Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ: MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A. 2008, 105 (5): 1516-1521.PubMed CentralView ArticlePubMedGoogle Scholar
- Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, Huang M, Shields DJ, Lindquist JN, Lapinski PE, et al: MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis. Nat med. 2010, 16 (8): 909-914.PubMed CentralView ArticlePubMedGoogle Scholar
- Jin W, Reddy MA, Chen Z, Putta S, Lanting L, Kato M, Park JT, Chandra M, Wang C, Tangirala RK, et al: Small RNA sequencing reveals MicroRNAs that modulate angiotensin II effects in vascular smooth muscle cells. J Biol Chem. 2012, 287 (19): 15672-15683.PubMed CentralView ArticlePubMedGoogle Scholar
- Fasanaro P, D’Alessandra Y, Di Stefano V, Melchionna R, Romani S, Pompilio G, Capogrossi MC, Martelli F: MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem. 2008, 283 (23): 15878-15883.PubMed CentralView ArticlePubMedGoogle Scholar
- Pulkkinen K, Malm T, Turunen M, Koistinaho J, Yla-Herttuala S: Hypoxia induces microRNA miR-210 in vitro and in vivo ephrin-A3 and neuronal pentraxin 1 are potentially regulated by miR-210. FEBS Lett. 2008, 582 (16): 2397-2401.View ArticlePubMedGoogle Scholar
- Wurdinger T, Tannous BA, Saydam O, Skog J, Grau S, Soutschek J, Weissleder R, Breakefield XO, Krichevsky AM: miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer cell. 2008, 14 (5): 382-393.PubMed CentralView ArticlePubMedGoogle Scholar
- Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, Chandrashekhar YS, Hall JL, Roy S, Zeng Y, et al: Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest. 2010, 120 (11): 4141-4154.PubMed CentralView ArticlePubMedGoogle Scholar
- Cordes KR, Sheehy NT, White MP, Berry EC, Morton SU, Muth AN, Lee TH, Miano JM, Ivey KN, Srivastava D: miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 2009, 460 (7256): 705-710.PubMed CentralPubMedGoogle Scholar
- Leeper NJ, Raiesdana A, Kojima Y, Chun HJ, Azuma J, Maegdefessel L, Kundu RK, Quertermous T, Tsao PS, Spin JM: MicroRNA-26a is a novel regulator of vascular smooth muscle cell function. J Cell Physiol. 2011, 226 (4): 1035-1043.PubMed CentralView ArticlePubMedGoogle Scholar
- Lagos D, Pollara G, Henderson S, Gratrix F, Fabani M, Milne RS, Gotch F, Boshoff C: miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator. Nat cell biol. 2010, 12 (5): 513-519.View ArticlePubMedGoogle Scholar
- Mulik S, Xu J, Reddy PBJ, Rajasagi NK, Gimenez F, Sharma S, Lu PY, Rouse BT: Role of miR-132 in angiogenesis after ocular infection with herpes simplex virus. Am J Pathol. 2012, 181 (2): 525-534.PubMed CentralView ArticlePubMedGoogle Scholar
- Katare R, Riu F, Mitchell K, Gubernator M, Campagnolo P, Cui Y, Fortunato O, Avolio E, Cesselli D, Beltrami AP, et al: Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132/novelty and significance. Circ Res. 2011, 109 (8): 894-906.PubMed CentralView ArticlePubMedGoogle Scholar
- Boucher JM, Peterson SM, Urs S, Zhang C, Liaw L: The miR-143/145 cluster is a novel transcriptional target of Jagged-1/Notch signaling in vascular smooth muscle cells. J Biol Chem. 2011, 286 (32): 28312-28321.PubMed CentralView ArticlePubMedGoogle Scholar
- Dentelli P, Rosso A, Orso F, Olgasi C, Taverna D, Brizzi MF: microRNA-222 controls neovascularization by regulating signal transducer and activator of transcription 5A expression. Arterioscler Thromb Vasc Biol. 2010, 30 (8): 1562-1568.View ArticlePubMedGoogle Scholar
- Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, Marks D, Obrietan K, Soderling TR, Goodman RH, et al: An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci U S A. 2008, 105 (26): 9093-9098.PubMed CentralView ArticlePubMedGoogle Scholar
- Harris TA, Yamakuchi M, Kondo M, Oettgen P, Lowenstein CJ: Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol. 2010, 30 (10): 1990-1997.PubMed CentralView ArticlePubMedGoogle Scholar
- Chen K, Rajewsky N: Deep conservation of MicroRNA-target relationships and 3’UTR motifs in vertebrates, flies, and nematodes. Cold Spring Harbor Symposia Quantitative Biol. 2006, 71: 149-156.View ArticleGoogle Scholar
- Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Doerks T, Stark M, Muller J, Bork P, et al: The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 2011, 39 (suppl 1): D561-D568.PubMed CentralView ArticlePubMedGoogle Scholar
- MicroRNA clinical trials from Clinical Trials.gov: http://clinicaltrials.gov/ct2/results?term=MICRORNA&Search=Search,
- Reesink HWJHLA, Zeuzem S, Lawitz E, Rodriguez-Torres M, Patel K, Chen A, Davis C, King B, Levin A, Hodges MR: Final Results - Randomized, Double-blind, Placebo-controlled Safety, Anti-viral Proof-of-Concept Study of Miravirsen, an Oligonucleotide Targeting miR-122, in Treatment-naïve Patients with Genotype1 (GT1) chronic HCV infection. In: 47th Annual Meeting of the European Association for the study of the liver: April 18-22. J Hepatol. 2012, 56 (suppl2): s26-View ArticleGoogle Scholar
- Garzon R, Marcucci G, Croce CM: Targeting microRNAs in cancer: rationale, strategies and challenges. Nat rev Drug discov. 2010, 9 (10): 775-789.PubMed CentralView ArticlePubMedGoogle Scholar
- Trang P, Weidhaas JB, Slack FJ: MicroRNAs as potential cancer therapeutics. Oncogene. 2008, 27 (Suppl 2): S52-S57.View ArticlePubMedGoogle Scholar
- Lima Walt F, Prakash Thazha P, Murray Heather M, Kinberger Garth A, Li W, Chappell Alfred E, Li Cheryl S, Murray Susan F, Gaus H, Seth Punit P, et al: Single-stranded siRNAs activate RNAi in animals. Cell. 2012, 150 (5): 883-894.View ArticlePubMedGoogle Scholar
- Yu D, Pendergraff H, Liu J, Kordasiewicz HB, Cleveland Don W, Swayze Eric E, Lima Walt F, Crooke Stanley T, Prakash Thazha P, Corey David R: Single-stranded RNAs Use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012, 150 (5): 895-908.PubMed CentralView ArticlePubMedGoogle Scholar
- Yancopoulos GD: Clinical application of therapies targeting VEGF. Cell. 2010, 143 (1): 13-16.View ArticlePubMedGoogle Scholar
- Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR: Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004, 351 (27): 2805-2816.View ArticlePubMedGoogle Scholar
- Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M: Targeted deletion of vegfa in adult mice induces vision loss. J Clin Invest. 2012, 122 (11): 4213-4217.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.