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Vascular Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / v p h
Review
“ApoptomiRs” in vascular cells: Their role in physiological and pathological angiogenesis Cristina Quintavalle a, Michela Garofalo b, Carlo M. Croce b, Gerolama Condorelli a,⁎ a b
Department of Cellular and Molecular Biology and Pathology, “Federico II” University of Naples, Biotechnological Science Faculty, and IEOS, CNR Naples, Italy Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
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Article history: Received 26 May 2011 Received in revised form 4 July 2011 Accepted 11 July 2011 Keywords: MicroRNA Cell death Endothelial cells
a b s t r a c t MicroRNAs (miRNAs) have emerged as crucial players regulating the magnitude of gene expression in a variety of organisms. This class of short (22 nucleotides) noncoding RNA molecules have been shown to participate in almost every cellular process investigated so far, and their deregulation is observed in different human pathologies including cancer, heart disease, and neurodegeneration. These new molecular regulators have been identified also in endothelial cells (ECs), and their role in the regulation of different aspects of the angiogenic process has been recently investigated in a variety of laboratories. The current review focuses on the research progress regarding the roles of miRNAs in vascular pathology and their potential therapeutic applications for vascular diseases associated with abnormal angiogenesis, such as cancer. © 2011 Elsevier Inc. All rights reserved.
Contents 1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Vascular consequences in response to arrest of miRNA biogenesis . . . 1.2. Role of Individual miRNA in angiogenesis and endothelial cell functions 1.3. MiRs and hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Tumor angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. MicroRNA and apoptosis in vascular cells . . . . . . . . . . . . . . . 1.6. Potential therapeutic applications . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Apoptosis, or programmed cell death, is an evolutionarily conserved mechanism of elimination of unwanted cells. This endogenous death machinery is triggered via two principal signaling pathways, namely the extrinsic ant the intrinsic pathway (Hengartner, 2000). The extrinsic pathway is activated by the engagement of death receptors on the cell surface. The binding of ligands such as Fas, tumor necrosis factor (TNF), or TNF-related apoptosis-inducing ligand (TRAIL) to cognate death receptors (DR) induces the formation of the death-induced signaling complex (DISC). The DISC in turn recruits
⁎ Corresponding author at: Dipartimento di Biologia e Patologia Cellulare e Molecolare & Facoltà di Scienze Biotecnologiche, Università degli Studi di Napoli “Federico II”, and IEOS, CNR, Via Pansini, 5. 80131 Naples, Italy. Tel.: + 39 081 7464416; fax: + 39 081 7463308. E-mail address:
[email protected] (G. Condorelli). 1537-1891/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2011.07.004
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caspase 8 and promotes the cascade of procaspase activation (Okada and Mak, 2004). The intrinsic pathway is triggered by various intracellular and extracellular stresses, whose signals converge mainly to the mitochondria (Ghobrial et al., 2005; Okada and Mak, 2004). The balance between pro-and anti-apoptotic members of apoptosis is crucial for the regulation of cell survival and cell death and thus for the physiological balance of tissue homeostasis (Fig. 1). miRNAs constitute a family of short non-coding RNA molecules of 20 to 25 nucleotides in length that regulate gene expression at the posttranscriptional level (Bartel, 2004). One miRNA is able to regulate the expression of multiple genes because it can bind to its messenger RNA targets in the transcript 3′ untranslated regions (3′ UTRs) as either an imperfect or a perfect complement (Gregory and Shiekhattar, 2005). Currently, more than 700 miRNAs have been cloned and sequenced in human, and the estimated number of miRNA genes is as high as 1000 in the human genome. Thus, a miRNA can be functionally as important as a transcription factor. MiRNAs may directly regulate at
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Extrinsic Pathway
Intrinsic Pathway
Ligand Various Apoptotic Stimuli
Death Receptor
Bim FADD
Bax Bak tBid
Caspase-8 Bid B AX
Activated Caspase-8
B AX
c yt c yt
c yt
Apaf-1
Caspase-9 Caspase-3
Apoptosis Fig. 1. Schematic representation of the apoptotic pathway — The extrinsic or caspase 8/10 dependent pathway is activated by ligand binding. The “death receptors” are specialized cell-surface receptors including Fas/CD95, tumor necrosis factor-alpha (TNF-alpha) receptor 1, and two receptors, DR4 and DR5, that bind to the TNF-alpha related apoptosisinducing ligand (TRAIL). The intrinsic pathway — also called mitochondrial pathway — is activated by various developmental cues or cytotoxic insults, and is strictly controlled by the BCL-2 family of proteins, caspase-9, apoptotic protease-activating factor-1 (APAF1) and cytochrome C release. The extrinsic and intrinsic pathways unite in the activation of caspase3, though the two pathways communicate through the pro-apoptotic Bcl-2 family member Bid before uniting at the shared activation of caspase-3.
least 30% of the genes in a cell. They are thus involved in the control of a wide range of biological functions and processes, such as development, differentiation, metabolism, growth, proliferation, and apoptosis (Garofalo et al., 2008, 2010; Lee and Dutta, 2006; Miska, 2005). It is well established that vascular diseases such as hypertension, atherosclerosis, and coronary artery disease, re-stenosis after angioplasty or transplantation, and diabetic vascular complication are among the leading causes of morbidity and mortality in developed countries. In addition, angiogenesis and re-endothelialization are also common vascular consequences in many diseases including cancer, atherosclerosis, and ischemic heart disease. Differentiation, contraction, migration, proliferation, and apoptosis of vascular smooth muscle cells (VSMCs) and/or endothelial cells (ECs) are critical cellular events responsible for the development of angiogenesis and vascular disease. Recent studies have demonstrated that miRNAs are highly expressed in vascular walls and their expression is deregulated in diseased vessels (Jamaluddin et al., 2011). In this review we will focus on the role of microRNA in the regulation of cell death and cell survival of vascular cells in physiological and pathological processes.
interfering with the expression of Dicer, a key enzyme involved in miRNA biogenesis, in vascular tissues and cells. Deletion of Dicer in vascular smooth muscle (VSM) resulted in a reduction in cellular proliferation and late embryonic lethality, associated with extensive internal haemorrhage. Blood vessels from VSM-deleted Dicer mice exhibited impaired contractility due to the loss of contractile protein markers (Pan et al., 2011). The knockdown of Dicer in ECs alters the expression of proteins that play a role in endothelial cell biology and angiogenic responses, such us Tie-2/TEK, VEGFR2, endothelial nitric oxide synthase (eNOS), interleukin-8, and angiopoietinlike 4 (ANGPTL4) (Suarez et al., 2007). The role of Dicer was also assed in vitro in human umbilical endothelial cells (HUVECs) and EA.hy.926 cells by specifically silencing Dicer using short interfering (si)RNA (Suarez et al., 2007). Interestingly, the expression of a combination of miR-17, miR-18a and miR-20a partially rescued the effect of Dicer deficiency. These findings clearly indicate a crucial role of miRNAs in the development and maintenance of cardiovascular system and clearly reflect the collective functions of many miRNAs rather than any single miRNA, indicating significant redundancy of miRNA function.
1.1. Vascular consequences in response to arrest of miRNA biogenesis
1.2. Role of Individual miRNA in angiogenesis and endothelial cell functions
The first series of observations establishing the key significance of miRNAs in the regulation of mammalian vascular biology came from experimental studies in which miRNA biogenesis was arrested by
Endothelial cell functions and angiogenesis are critically regulated by microRNAs such as miR-126 and the miR-17–92 cluster in vitro and in
vivo. MiR-126 is an endothelial specific microRNA and is a key positive regulator of angiogenic signaling and vascular integrity in vivo. It is encoded by an intron of the epidermal growth factor-like domain 7 gene. Knockdown of miR-126 during zebrafish embryogenesis or deletion of miR-126 in mice resulted in defects in vascular development. Mice deficient in miR-126 exhibited delayed angiogenic sprouting, widespread haemorrhaging, and partial embryonic lethality. In addition, miR-126 mutant mice that successfully completed embryogenesis displayed diminished angiogenesis accompanied by leaky blood vessels and increased mortality after coronary ligation, a model for myocardial infarction. Endothelial cells deficient in miR-126 failed to respond to angiogenic factors, including VEGF, epidermal growth factor (EGF), and bFGF. Two direct targets of miR-126 are Sprouty-related EVH1 domaincontaining protein 1 (Spred1) and a regulatory subunit of PI3K, PIK3R2 (also known as p85β). These observations indicate that miR-126 is induced by blood flow and controls angiogenic sprouting by the stimulation of VEGF. The polycistronic microRNA-17–92 cluster comprises seven mature micro-RNAs (miR-17-5p and -3p, miR-18a, miR-19a and b, miR-20a and miR-92a). The overexpression of this cluster has been linked to different types of human cancer and tumor angiogenesis. Recently it has been suggested a role for miR-17–92 also in cardiac development, in endothelial cell proliferation and revascularization. MiR-17 transgenic mice showed a reduced heart weight and motility of myocytes probably through downregulation of fibronectin, an extracellular matrix protein, which promotes cell adhesion, proliferation and tissue development (Shan et al., 2009). Furthermore, Bonauer and colleagues demonstrated that miR-17–92 cluster is highly expressed in human endothelial cells. Forced expression of miR-92a in endothelial cells blocked angiogenesis in vitro and in vivo targeting several proangiogenetic proteins. Otherwise in mouse models, systemic administration of miR-92a inhibitor leads to enhanced blood vessels growth and functional recovery of damage tissue (Bonauer et al., 2009). In the retinal angiogenesis a crucial role is played by miR-218 encoded by an intron of the Slit-1 and Slit-2 genes, through the targeting of multiple components of the heparan sulfate biosynthetic pathway (Small et al., 2010). Recent studies demonstrated that miRNA-100 modulates proliferation, tube formation, and sprouting activity of endothelial cells and migration of vascular smooth muscle cells functioning as an endogenous repressor of the serine/threonine protein kinase mammalian target of rapamycin (mTOR). Other miRNAs also promote angiogenesis in cultured endothelial cells. For example, endothelial cells exposed to serum overexpress miR-130a, which targets the antiangiogenic homeobox genes HOXA5 and GAX (Chen and Gorski, 2008). miR-210 directly modulates the TKR ligand EFNA3, a repressor of VEGF-dependent endothelial cell migration and tubulogenesis (Fasanaro et al., 2008). Co-cultured endothelial cells overexpress miR-296 in response to VEGF stimulation, which promotes antigenic signaling by degrading VEGF receptor and PDGF receptor via HGF substrate repression. MiR-221 and miR-222 inhibit stem cell factor (SCF)-dependent angiogenesis by decreasing the abundance of c-KIT, a ligand for the SCF receptor. Moreover, miR-221 negatively regulates angiogenesis in endothelial cells up-regulating the growth arrest specific homeobox gene (GAX) (Chen et al., 2010). MiR-222 negatively modulates vascular remodelling in endothelial cells through STAT5A expression (Dentelli et al., 2010). In contrast, miR-27b, miR-132, and miR-210 and Let-7f are proangiogenic, since inhibition of these microRNAs reduces angiogenesis.
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proangiogenic activity because of its targeting of ephrin A3, a repressor of VEGF-dependent endothelial cell migration and formation of capillarylike structures. Recently results demonstrate that miR-200b is involved in enabling the hypoxia-induced angiogenic response. In fact under hypoxic conditions miR-200b down-regulation is required to relieve Ets-1 repression, a key transcription factor that supports angiogenesis, resulting in successful angiogenic outcomes (Chan et al., 2011). Hypoxia could also down-regulate miR expression. Inhibition of transcription or accelerating miR degradation has been proposed as possible mechanisms of downregulation of miRs under a low oxygen environment. In cardiac myocytes, hypoxia suppressed the expression of mature miR-199a (Rane et al., 2009). The study of Kim (Won Kim et al., 2009) demonstrated that ischemic preconditioning (IP) of stem cells by multiple short episodes of ischemia/reoxygenation (I/R), induced the expression of miR-210. MiR-210 plays a key role in bone marrow-derived mesenchymal stem cell (MSC) survival. One of his targets is the caspase-8-associated protein-2 (Casp8ap2).
1.4. Tumor angiogenesis Angiogenesis is the main mechanism by which new blood vessels are formed during physiological processes like wound healing, inflammation, and the female reproductive cycle. However, angiogenesis is involved in various disorders including age-related macular degeneration, rheumatoid arthritis, endometriosis, and cancer (Hanahan and Weinberg, 2011; Risau, 1997). Angiogenesis occurs around tumors mainly through the production by the cancer cells of pro-angiogenesis factors that stimulate neovascularization like the vascular endothelial growth factor (VEGF). MiRNAs are important modulators of tumor-induced neoangiogenesis. MiRs may regulate angiogenesis by targeting vessels promoting factors such as VEGF, or by regulating cell death. A group of miRNAs including miR-16, miR-15b, miR-20a, and miR-20b modulate VEGF under hypoxic conditions (Hua et al., 2006). Otherwise, miR-126 had opposite biological effect on VEGF regulation in different cell types. In lung cancer cells miR-126 directly repressed VEGF expression in vitro and in vivo (Liu et al., 2009). Contrarily, in endothelial cells miR-126 expression was upregulated during angiogenesis and repressed negative regulators of the VEGF pathway (Fish et al., 2008). MicroRNAs may promote tumor angiogenesis also by regulating cell death. It has been recently described that miR-378 enhances cell survival, reduces caspase-3 activity, and promotes tumor growth and angiogenesis through repression of the expression of two tumor suppressors, Sufu and Fus-1. Studies in mice demonstrated that miR-519c-overexpressing cells exhibited dramatically reduced HIF1A
miR-17~92 miR-130 a miR-100 miR-210 miR-21 miR-26 a Proliferation
miR-221 miR-222
Cell Death
Blood Flow
Endothelial cell
1.3. MiRs and hypoxia The abundance of microRNAs in endothelial cells may change in response to changes of environment, including exposure to hypoxia. For example, hypoxia triggers the production of miR-210, which has
Fig. 2. Schematic representation of miRs involved in the regulation of vascular cell death or proliferation — Endothelial and muscle cells are under control of miRs function. Some microRNAs like miR-100, miR-21 or miR-26a control positively cell proliferation and angiogenesis; conversely miR-221 and miR-222 regulate negatively the proliferation of endothelial cells.
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levels, which was followed by suppressed tumor angiogenesis, growth, and metastasis in the mice (Cha et al., 2010). 1.5. MicroRNA and apoptosis in vascular cells Several studies demonstrated that miRNAs play significant roles in apoptosis regulation in different types of cells (Fig. 2). These miRs could be named “ApoptomiR”. One of the most well-known antiapoptotic apoptomiR is miR-21. Expression of this miRNA is upregulated in many cancer types and it represses the expression of apoptosis-related genes such as PTEN (Meng et al., 2007), PDCD4 (Asangani et al., 2007), and TPM1 (Zhu et al., 2007). miR-21 is a highly expressed microRNA (miRNA) in cardiovascular system and is one of the most upregulated miRNAs in the vascular wall, after balloon injury (Ji et al., 2007). Recent studies have revealed that its expression is deregulated in heart and vasculature under cardiovascular disease conditions such as proliferative vascular disease, cardiac hypertrophy, and ischemic heart disease. miR-21 is found to play important roles in vascular smooth muscle cell proliferation and apoptosis. Inhibition of miR-21 expression significantly decreased neointima formation after angioplasty. This effect was related to the decrease in cell proliferation and increase in cell apoptosis (Cheng et al., 2007). In the same way, Weber and colleagues demonstrated that miR-21 has an important role in shear stress-induced changes in EC function. In fact, in HUVECs miR-21 overexpression leads to decreased apoptosis and increased eNOS phosphorylation and nitric oxide production. The involvement of miR-21 in ROS pathway was also assessed by other groups which reported that miR-21 was upregulated in smooth muscle cells (VSMCs) after treatment with hydrogen peroxide and mediated its effect through PDCD4 (programmed cell death-4 . Interestingly, miR-21 is induced by IL-6, suggesting that it is essential in the protection against inflammationinduced apoptosis (Löffler et al., 2007). During a plaque destabilization or atherosclerosis, apoptosis is a crucial phenomenon. In response to vascular damage, the chemokine CXCL-12 and its receptor CXCR-4 are up-regulated and counteract apoptosis recruiting progenitor cells. During the atherosclerotic process, miR-126 expression decreases and triggers a feedback loop that increases CXCL-12 production and cell survival. In particular in this process, apoptotic bodies from endothelial cells, which are usually engulfed by phagocytes, contain mainly miR-126. Interestingly, incubation of those apoptotic bodies with HUVECs results in transfer of miR-126 into recipient cells. In mice administration of apoptotic bodies or miR-126 limited atherosclerosis (Zernecke et al., 2009). All those and other observations (Hristov et al., 2004), indicate that during atherosclerosis, apoptotic bodies produced by endothelial cells, have a crucial role since they induce progenitor cell differentiation and proliferation. Recently Leeper et al.(2011) have also indicated that miR-26a inhibit vascular smooth muscle cells differentiation and apoptosis and promote proliferation and migration possibly interfering with TGF-b/BMP pathway. 1.6. Potential therapeutic applications The discovery of miRNAs involved in endothelial cell biology has opened exciting new hopes for targeted anti-angiogenesis cancer therapy. A miR-based therapy may be designed as a method for delivering anti-angiogenesis miRNAs to sites of tumor angiogenesis, for delivering anti-atherosclerosis miRs, or miRs with the capability of reducing ischemia of cardiac cells. The approach may include the delivering of the miRs, for targeting the expression of proteins that antagonize the proper execution of the angiogenesis program or alternatively, the delivery of compounds that inhibit the activity of miRNAs, the antagomiRs. One example of this kind of approach is the study of Van Solingen et al.(2009) which showed that injecting mice with antagomiR-126 reduces ischemia-induced angiogenesis.
However, a potential pitfall of miRNA based therapy is the off target effects due to complementarities to multiple substrates. In addition, miRNAs have been shown to induce opposing effects depending on e.g. cell type. A major challenge will be to engineer molecules that target a specific miRNA thereby limiting off-target effects. In addition, it was recently reported that glioblastoma cells release micro-vesicles to deliver proteins and genetic information like miRNAs to neighbouring cells (Lee et al., 2011). Targeting such microvesicles to the tumor endothelium for delivery of miRNA based therapy will be a future challenge. Chemical modifications of either miRNAs or antago-miRs could greatly enhance their efficiency. For example, conjugation of cholesterol to oligonucleotides has been shown to enhance their cellular uptake. Other modifications include the use of locked nucleotides (LNA), or the conjugation of 2′-Omethoxyethyl phosphorothioate (2′-MOE). All these strategies have proven successful to reduce plasma cholesterol levels using miR-122 antagonists (Li et al., 2011). Acknowledgements This work was partially supported by funds from Associazione Italiana Ricerca sul Cancro, AIRC to GC (grant 10620), MERIT (RBNE08E8CZ_002), and by the Sidney Kimmel Cancer Research Foundation (MG). C.Q. is recipient of a FIRC (Federazione Italiana Ricerca sul Cancro) fellowship. References Asangani, I.A., et al., 2007. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27, 2128–2136. Bartel, D.P., 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297. Bonauer, A., et al., 2009. MicroRNA-92a Controls Angiogenesis and Functional Recovery of Ischemic Tissues in Mice, pp. 1710–1713. Cha, S.-T., et al., 2010. MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis, pp. 2675–2685. Chan, Y.C., et al., 2011. miR-200b Targets Ets-1 and Is Down-regulated by Hypoxia to Induce Angiogenic Response of Endothelial Cells, pp. 2047–2056. Chen, Y.D., Gorski, H., 2008. Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5, pp. 1217–1226. Chen, Y., et al., 2010. Regulation of the Expression and Activity of the Antiangiogenic Homeobox Gene GAX/MEOX2 by ZEB2 and MicroRNA-221, pp. 3902–3913. Cheng, Y., et al., 2007. MicroRNAs are aberrantly expressed in hypertrophic heart: do they play a role in cardiac hypertrophy? Am. J. Pathol. 170, 1831–1840. Dentelli, P., et al., 2010. MicroRNA-222 Controls Neovascularization by Regulating Signal Transducer and Activator of Transcription 5A Expression, pp. 1562–1568. Fasanaro, P., et al., 2008. MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3, pp. 15878–15883. Fish, J.E., et al., 2008. miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 15, 272–284. Garofalo, M., et al., 2008. MicroRNAs in diseases and drug response. Curr. Opin. Pharmacol. 8, 661–667. Garofalo, M., et al., 2010. MicroRNAs as regulators of death receptors signaling. Cell Death Differ. 2010, 2. Ghobrial, I.M., et al., 2005. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin. 55, 178–194. Gregory, R., Shiekhattar, I.R., 2005. MicroRNA biogenesis and cancer. Cancer Res. 65, 3509–3512. Hanahan, D., Weinberg, Robert A., 2011. Hallmarks of cancer: the next generation. Cell 144, 646–674. Hengartner, M.O., 2000. The biochemistry of apoptosis. Nature 407, 770–776. Hristov, M., et al., 2004. Apoptotic Bodies from Endothelial Cells Enhance the Number and Initiate the Differentiation of Human Endothelial Progenitor Cells In Vitro, pp. 2761–2766. Hua, Z., et al., 2006. MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS One 1, e116. Jamaluddin, M.S., et al., 2011. miRNAs: Roles and Clinical Applications in Vascular Disease, pp. 79–89. Ji, R., et al., 2007. MicroRNA Expression Signature and Antisense-Mediated Depletion Reveal an Essential Role of MicroRNA in Vascular Neointimal Lesion Formation, pp. 1579–1588. Lee, Y., Dutta, A., 2006. MicroRNAs: small but potent oncogenes or tumor suppressors. Curr. Opin. Investig. Drugs 7, 560–564. Lee, T., et al., 2011. Microvesicles as mediators of intercellular communication in cancer —the emerging science of cellular ‘debris’. Semin. Immunopathol. 1–13. Leeper, N.J., et al., 2011. MicroRNA-26a is a novel regulator of vascular smooth muscle cell function. J. Cell. Physiol. 226, 1035–1043.
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