Table 1.
miRNAs playing a role in cardiovascular neovascularisation.
| miRNA | Model | Effect | Experimentally confirmed molecular targets | References |
|---|---|---|---|---|
| miRNAs THAT IMPROVE NEOVASCULARISATION | ||||
| miR-10a/10b | miR-10a and miR-10b deficient & WT zebrafish embryos | Impaired blood vessel outgrowth in miR-10a and miR-10b deficient zebrafish embryos compared with controls | mindbomb E3 ubiquitin protein ligase 1 (mib1) | Wang et al., 2016 |
| miR-21 | Cardiac microvascular endothelial cells (CMVECs) Sprague-Dawley rats -MI induction by LAD coronary artery ligation Chicken chorioallantoic membrane (CAM) |
Increased EC tube formation, proliferation and decreased apoptosis post-miR21 overexpression in-vitro. Improved cardiac function post-miR-21 overexpression in rats. Opposite effects post-miR inhibition in-vivo. Implantation of matrigel plugs containing miR-21-overexpressing DU145 cancer cells onto the CAM of a chicken embryo resulted in increased microvessel formation compared to controls | Phosphatase and tensin homolog (PTEN) | Liu et al., 2011; Yang et al., 2016 |
| miR-26b | HUVECs Male CD-1 mice-HLI induction post-left femoral artery ligation |
Increased EC proliferation, migration and tube formation post-miR overexpression in-vitro. Decreased EC proliferation and tube formation post-miR-inhibition in-vitro. Increased microvessel formation in a Matrigel plug model. Overexpression of miR-26b in a mouse HLI model improved capillary survival in the ischaemic muscles | PTEN | Martello et al., 2018 |
| miR-23-24-27 cluster (miR-23a/b, miR-27a/b, miR-27a-3p) |
HUVECs EC spheroids miR-27b knock-out & WT zebrafish embryos aortic rings from athymic nude mice FVB mice-HLI induction C57/Bl6 mice- MI induction by LAD coronary artery ligation |
Decreased EC sprouting in aortic rings ex-vivo post-miR-27b knock-down. Impaired capillary branching in miR-27b knock-out zebrafish embryos compared with controls. Increased capillary density and reperfusion post-miR-27b injection in mouse HLI and MI models compared with controls. Inhibition of miR-23a/b and miR-27a/b in HUVECs significantly impaired their tube formation ability. Aortic ring treatment with anti-miR-23 or anti-miR-27 resulted in impaired EC sprouting. Opposite results post miR-23b and miR-27b overexpression. Overexpression of miR-27a-3p in HUVECs significantly increased tube formation. Opposite results post-miRNA inhibition. Overexpression of miR-27a or miR-27b in EC spheroids, resulted in significantly increased EC sprouting compared to controls. MiR-27a/b inhibition led to opposite results. | Spry-2 (target of both miR-23 and miR-27) Dll4 (target of miR-27b) Semaphorin 6A (SEMA6A) (target of both miR-23 and miR-27) |
Zhou et al., 2011; Biyashev et al., 2012; Veliceasa et al., 2015; Rao et al., 2019 |
| miR-29a | HUVECs | Increased EC tube formation and proliferation post-miR overexpression in-vitro. Opposite effects were observed post-miR inhibition in EC in-vitro | HMG-Box Transcription Factor 1 (HBP1) | Yang et al., 2013 |
| miR-30a | Transgenic (Tg) friend leukaemia integration 1 transcription factor (fli1): enhanced green fluorescent protein (EGFP) zebrafish | MiR-30a loss of function decreased arteriolar sprouts compared to controls. miR-30a gain of function increased arteriolar branching | Dll4 | Jiang et al., 2013 |
| miR-31 miR-720 |
EPCs from patients with CHD nude mice- HLI induction by ligation of both proximal and distal portion of the right femoral artery, as well as the distal portion of saphenous artery |
Increased tube formation and migration of EPC post-miR-31/−720 overexpression. Opposite effects were observed post-miR inhibition. Increased blood flow by intramuscular injection of EPCs overexpressing miR-31 | Thromboxane A2 receptor (miR-31 target) Vasohibin-1 (miR-720 target) |
Wang et al., 2014 |
| miR-101 | HUVECs Aortic rings from female C57BL/6J mice Female C57Bl/6J mice- HLI induction by double ligation of the superficial femoral artery proximal to the deep femoral artery and distal femoral artery |
Increased EC tube formation, proliferation and migration in-vitro post-miR-101 overexpression in-vitro. Increased EC sprouting ex-vivo post-transfection with mir-101-expressing lentivirus. Increased capillary density and limb perfusion in miR-101 injected mice compared with controls | CUL 3 | Kim et al., 2014 |
| miR-106b-93-25 cluster (miR-106b) |
Primary bone marrow stromal cells (BMSCs) from Female WT & miR-106b~25 knock-out mice Aortic rings from mir-106b~25 wild-type or knock-out mice Female WT & miR-106b~25 KO mice—HLI induction by femoral artery ligation |
Increased tube formation ability and survival of BMSCs from WT compared to BMSCs from miR-106b~2 knock-out mice. Increased capillary sprouting in WT compared to miR-106b~2 knock-out mice. Significantly increased blood flow and number of lectin-positive capillaries in the WT compared with the KO mice on Day 7 & Day 14 post-ischaemia | Unknown | Semo, 2013 |
| miR-126 | Human aortic endothelial cells (HAECs) HUVEC Aortic rings from miR-126−/− mice Male NMRI nude mice- MI induced by LAD coronary artery ligation miR-126−/− mice- MI induced by LAD coronary artery ligation |
Improved HAEC tube formation post-miR-126 transfection in-vitro. Opposite effects post-miR inhibition in-vitro. Improved HUVEC tube formation post-miR-126-expressing adenovirus (Ad-miR-126) transfection in-vitro. Opposite effects were observed post-miR inhibition in-vitro. Impaired EC sprouting in aortic rings from miR-126−/− mice ex-vivo. Improved cardiac function and capillary density post-miR-126 mimic injection in NMRI nude mice post-MI. Opposite effects post-miR inhibition in-vivo. Reduced survival of miR-126−/− mice post-MI (half of the mice died 1week post-MI, and nearly all of them died within 3 weeks post-MI) | SPRED1 PIK3R2 |
Fish et al., 2008; Wang et al., 2008; Jakob et al., 2012 |
| miR-130a | HUVECs | HUVEC co-transfection with pcDNA3.1-miR-130a and pcDNA3.1-growth-arrest-homeobox-transcription-factor (GAX) showed that miR-130a antagonised GAX-induced inhibition of HUVEC tube formation and migration, increasing tube formation and migration in-vitro. miR-130a inhibitor reversed antagonism of GAX activity | GAX | Chen and Gorski, 2008 |
| miR-132 | HUVECs | Increased HUVEC tube formation ability and proliferation post-miR overexpression. Opposite effects were observed post-miR inhibition in EC in-vitro | p120 Ras GTPase activating protein (p120RasGAP) | Anand et al., 2010 |
| miR-150 | HUVECs exposed to oxidised low-density lipoprotein (LDL) Apolipoprotein E-deficient (ApoE−/−) mice-HLI induction by femoral artery ligation |
Overexpression of miR-150 rescued the decreased tube formation ability of HUVECs exposed to LDL. Intramuscular injection of miR-150 mimic increased capillary and arteriolar (arteriogenesis) densities compared with controls | SRC Kinase Signalling Inhibitor 1(SRCIN1) (previously identified target) | Desjarlais et al., 2017 |
| miR-210 | Human umbilical vein endothelial cells (HUVECs), Aortic rings from female C57BL/6 mice, miR-210 overexpressing & WT mice subjected to cardiac ischaemia/reperfusion or permanent LAD coronary artery ligation |
Increased HUVEC tube formation post-miR210 overexpression in-vitro. Opposite effects were observed post-miR inhibition in-vitro. Increased EC sprouting in aortic rings from miR-210 overexpressing mouse hearts ex-vivo. Increased reperfusion, capillary density and improved cardiac function in miR-210 overexpressing mice compared with controls both after ischaemia-reperfusion and MI induction | Ephrin-A3 | Hu et al., 2010; Arif et al., 2017 |
| 14q32 cluster (miR-329, miR-487b, miR-494, and miR-495) |
Male C57BI/6 mice-HLI induction by electroagulation of the left femoral artery proximal to the superficial epigastric arteries (single ligation-model for effective arteriogenesis), or by electroagulation of the distal femoral artery proximal to the bifurcation of the popliteal and saphenous artery (double ligation-model for severe peripheral arterial disease) | Silencing of miRNAs was induced by gene silencing oligonucleotides (GSO). Treatment with all 4 GSO improved blood flow recovery post-ischaemia in-vivo. GSO-495 and GSO-329 treatment increased perfusion 3 days post-ischaemia. Treatment with GSO-329 only, increased perfusion 7 days post-ischaemia. Increased collateral artery diameters (arteriogenesis) and capillary densities post-GSO treatment in mice compared with controls | Myocyte enhancer factor 2A (MEF2a) (target of miR-329) FGFR2, VEGF-A, ephrin-2 (targets of miR-494) |
Welten et al., 2014 |
| miR-424 | HUVECs | Increased tube formation, migration and proliferation of EC in-vitro post-miRNA overexpression. Opposite effects were observed post-miR inhibition in EC in-vitro | Cullin 2 (CUL2) | Ghosh et al., 2010 |
| miR-503 | HUVECs Human microvascular endothelial cells (HMVECs) |
Increased tube formation and migration of EC in-vitro post-miRNA overexpression. Opposite results were observed post-miR inhibition in EC in-vitro | Cyclin E1 (CCNE1) Cell division cycle 25 A (cdc25A) |
Caporali et al., 2011 |
| let-7f | HUVECs | Decreased tube formation and migration of EC in-vitro post-miRNA inhibition | Unknown | Kuehbacher et al., 2007 |
| miRNAs THAT INHIBIT NEOVASCULARISATION | ||||
| miR-15a/ miR-16-1 cluster (miR-15a, miR-16) |
HUVECs EC-selective MiR-15a Transgenic (EC-miR-15a TG) & WT mice- HLI induction by femoral artery ligation Male CD1 mice- LI induction by left femoral artery ligation |
Increased HUVEC tube formation and migration post-miR inhibition in-vitro. Opposite results post-miR-overexpression in-vitro. Decreased number of capillaries and blood perfusion in EC-miR-15a TG mice compared with controls. Inhibition of miR-15a/16 in mice post HLI improved capillary density and blood perfusion | FGF2 VEGF |
Yin et al., 2012; Besnier et al., 2019 |
| miR-15b-5p | HUVEC Male C57BL/6 mice- HLI induction by left femoral artery ligation |
Decreased HUVEC tube proliferation and migration post-miR overexpression in-vitro. Decreased blood flow recovery, capillary and arterial density in HLI mice post-miR-15b-5p overexpression | AKT Serine/Threonine Kinase 3 (AKT3) | Zhu et al., 2017 |
| miR-16 miR-426 |
HUVECs | Decreased EC tube formation and migration post-miR overexpression in-vitro | VEGF receptor-2 (VEGFR2) (target of both miRNAs) Fibroblast growth factor receptor-1 (FGFR1) (target of both miRNAs) |
Chamorro-Jorganes et al., 2011 |
| miR-22 | Fluorescent-labelled transgenic zebrafish Tg(fli1:EGFP) embryo expressing GFP in ECs | MiR-22 injection in zebrafish embryos resulted in defective vascular development which was rescued with miR-22 and VE-cadherin co-injection. miR-22 negative control (NC) injection in zebrafish embryos resulted in normal vessel development | Vascular endothelial (VE)-cdh | Gu et al., 2017 |
| miR-23-24-27 cluster (miR-24) |
HUVEC Tg(kdrl:eGFP)s843 zebrafish embryos Male C57BL/6 mice- MI induction by LAD coronary artery ligation |
Decreased HUVEC tube formation, proliferation and migration post-miR overexpression in-vitro. Increased vascular defects in miR-24–overexpressing zebrafish compared with controls. Increased capillary and arteriolar density post-miR-24 inhibition in a MI mouse model | PAK4 GATA2 |
Fiedler et al., 2011 |
| miR-23-24-27 cluster (miR-24-3p) |
HUVECs Male CD1 mice-HLI model induction by left femoral artery ligation |
Decreased EC survival, tube formation and proliferation post-transfection with pre-miR-24-3p in-vitro. Opposite results post-miR inhibition in-vitro. Increased capillary density post-miR inhibition in-vivo, but decreased blood perfusion since the new vessels appeared disorganised and twisted | Notch1 Dll1 |
Marchetti et al., 2020 |
| miR-26a | HUVECs flk:eGFP zebrafish embryos Male C57BL/6 mice- MI induction by LAD coronary artery ligation |
Decreased HUVEC tube formation and migration post-miR overexpression in-vitro. Overexpression of miR-26a in zebrafish impaired the development of caudal vein plexus (CVP) axial vein. Reduced infarct size and increased number of CD31+ cells after miR-26a inhibition in mice post-MI | SMAD Family Member 1 (SMAD1) | Icli et al., 2013 |
| miR-34 | Male C57BL/6 mice- MI induction by LAD coronary artery ligation | Improved cardiac function, capillary density and left ventricle remodelling post-inhibition of miR-34 in-vivo compared with controls | Unknown | Bernardo et al., 2012 |
| miR-17-92 Cluster (miR-92a) |
Pig-ischaemia/reperfusion induction (percutaneous transluminal coronary angioplasty balloon was placed in the LAD artery distal to the first diagonal branch for 49-60 minutes MiR-92a–deficient mice- MI induction by LAD coronary artery ligation C57Bl/6 mice-MI induction by LAD coronary artery ligation & HLI induction by ligation of the superficial and deep femoral artery and vein |
Increased capillary density and reduced cardiac inflammation and post-mir-92α inhibition in mouse and pig MI models and in a HLI mouse model compared with controls | INTGA5 | Bonauer et al., 2009; Hinkel et al., 2013; Bellera et al., 2014 |
| miR-100 | HUVECs C57/Bl6J mice- HLI induced by double ligation of the superficial femoral artery proximal to the deep femoral artery and distal femoral artery |
Increased HUVEC tube formation, proliferation and migration post-miR inhibition in-vitro. Opposite effects were observed post-miR-overexpression in-vitro. Increased perfusion and capillary and arterial density post-miR-100 inhibition in-vivo compared with controls | Unknown | Grundmann et al., 2011 |
| miR-124 | HUVEC Male C57BL/6 mice- thoracic aorta constriction (TAC) |
Increased HUVEC tube formation, proliferation and migration post-miR inhibition in-vitro. Opposite effects were observed post-miR-overexpression in-vitro. Impaired cardiac function and blood flow in intravenous adeno-associated virus (AAV)-miR-124-injected mice compared with controls | CD151 | Zhao et al., 2018 |
| miR-132/212 | HUVEC Mice- HLI induced by double ligation of the superficial femoral artery proximal to the deep femoral artery and distal femoral artery |
Decreased tube formation and migration of EC in-vitro post-miRNA overexpression. Opposite effects were observed post-miRNA inhibition. Increased capillary and arterial density post-miRNA inhibition in-vivo | RAS p21 protein activator 1 (Rasa1) (previously identified target of miR-132) SPRED1 (target of both miRNAs) Spry1 (target of both miRNAs) |
Lei et al., 2015 |
| miR-135-3p | HUVEC | Increased HUVEC tube formation, proliferation and migration post-miR inhibition in-vitro. Opposite effects were observed post-miR-overexpression in-vitro | Huntingtin-interacting protein 1 (HIP1) | Icli et al., 2019b |
| miR-142a-3p | Tg(fli1:EGFP)y1 zebrafish embryos expressing GFP in ECs | Loss of vascular integrity, haemorrhage and vascular remodelling post-injection of miR-142a-3p in zebrafish embryos. Normal primary vasculature but defective intersegmental vessels (Se) and abnormal remodelling in miR-142a-3p knock-out embryos | Cdh5 (VE-cdh) | Lalwani et al., 2012 |
| miR-143/145 cluster (miR-143, miR-145) |
HUVECs | Increased HUVEC tube formation and proliferation post-miR inhibition. Opposite results post-miR-143/-145 overexpression in-vitro | Hexokinase II (HKII) (miR-143 target) Integrin β (miR-145 target) |
Climent et al., 2015 |
| miR-183 cluster (miR-96, miR-182, miR-183) |
Mouse cardiac endothelial cells (MCECs) HCMECs C57BL/6N mice -MI induction by LAD coronary artery ligation miR-96/miR-183 knock-out mice -MI induction by LAD coronary artery ligation |
Overexpression of miR-96 and/or miR183 reduced tube formation and proliferation, but no migration of neonatal MCECs in-vitro. Inhibition of miR-183 cluster improved tube formation, proliferation and migration of adult MCECs in-vitro. Inhibition of miR-96 and miR-183 increased tube formation and proliferation of adult MCEC in-vitro, whereas miR-182 inhibition did not affect these measures. Similarly, overexpression of miR-96 and miR-183 in HCMECs reduced tube formation and proliferation, whereas dual inhibition of these miRs increased both parameters. Injection of miR-96 and miR-183 mimics in neonatal mice post-MI decreased vascularisation around the fibrotic tissue and increased the retention of scar tissue. MI induction in miR-96/miR-183 knockout mice resulted in increased capillary and arteriole densities, nut cardiac function and fibrosis did not change significantly compared to the WT controls. | Anillin (ANLN) | Castellan et al., 2020 |
| miR-185 | HMVECs | Decreased HMVEC tube formation, proliferation and migration post-miR overexpression. Opposite results post-miR-inhibition in-vitro | Stromal interaction molecule 1 (STIM1) | Hou et al., 2016 |
| miR-199a-5p | Bovine aortic endothelial cell (BAEC) | Increased EC tube formation post-miRNA inhibition in-vitro | VEGFA (target in HEK293 cells) Calcineurin (target in HEK293 cells) SOD1 (target in HEK293 cells |
Joris et al., 2018 |
| miR-214 | EPCs HUVECs Mice-HLI induction by right femoral artery and the distal portion of saphenous artery ligation C57BL/6 mice- TAC restriction |
Increased EPC tube formation post-miR inhibition. Increased HUVEC tube formation, proliferation and migration post-miR inhibition. Opposite results post-miR-214 overexpression in-vitro. Increased blood flow by transplantation of EPC, in which miR-214 was inhibited, to the ischaemic limb tissue. Improved cardiac function and increased number of capillaries post-AAV9-anti-miR-214 injection compared with controls | X-box binding protein 1 (XBP1) | Duan et al., 2015; Jin et al., 2015 |
| miR-217 | HUVECs HAECs HCAECs |
Decreased EC tube formation and migration post-miR overexpression in-vitro. Opposite results post-miR-inhibition in-vitro | Silent Information Regulator 1 (SirT1) (target of miR-217) | Menghini et al., 2009 |
| miR-221/222 | HUVECs | Decreased HUVEC tube formation and migration post-miR overexpression in-vitro | Signal transducer and activator of transcription 5A (STAT5A) (miR-222 target) | Poliseno et al., 2006; Dentelli et al., 2010 |
| miR-342-5p | HUVEC mouse aortas from endothelial-specific Notch-activating mice |
Decreased HUVEC tube formation and migration post-miR overexpression in-vitro. Decreased EC sprouting in aortic rings post-miR mimic transfection ex-vitro | Endoglin | Yan et al., 2016 |
| miR-483-5p | HUVECs | Decreased HUVEC tube formation and migration post-miR overexpression. Opposite results post-miR-inhibition in-vitro | Serum response factor (SRF) | Qiao et al., 2011 |
| miR-615-5p | HUVEC C57BL/6 mice-HLI induced by femoral artery ligation |
Increased HUVEC tube formation, proliferation and migration post-miR inhibition in-vitro. Opposite effects were observed post-miR-overexpression in-vitro. Improved blood flow recovery and capillary density post-miRNA inhibition in-vivo | IGF-2 Ras-associating domain family member 2 (RASSF2) |
Icli et al., 2019a |
| miR-665 | HUVECs Human cardiac microvascular endothelial cells (HCMVECs) Male C57BL/6 mice- TAC restriction |
Decreased HUVEC tube formation, proliferation and migration post-miR overexpression in-vitro. Opposite results post-miR-inhibition in-vitro. Increased coronary microvessel density and improved heart function post-miR-665 inhibition in vivo | Ago2 | Fan et al., 2018 |
| miR-939 | HUVECs | Decreased HUVEC tube formation, proliferation and adhesion, but increased migration post-miR overexpression in-vitro. Opposite results post-miR-inhibition in-vitro | γ-catenin | Hou et al., 2017 |
| miRNAs WITH OPPOSITE IN-VITRO AND IN-VIVO FUNCTIONS | ||||
| miR-146a | HUVEC Balb/c mice-femoral artery ligation |
Impaired EC tube formation and proliferation post-miRNA inhibition in-vitro. In vivo, miRNA inhibition post-femoral artery ligation did not affect capillary density but significantly increased collateral artery diameter (arteriogenesis) | Unknown | Heuslein et al., 2018 |
| miR-155 | HUVECs Aortic rings from miR-155−/− mice C57/BL6J mice- HLI induction by double ligation of the superficial femoral artery proximal and distal to the deep femoral artery miR-155−/− mice- HLI induction by double ligation of the superficial femoral artery proximal and distal to the deep femoral artery |
Increased HUVEC tube formation and proliferation post-miRNA inhibition in-vitro. Decreased EC sprouting in aortic rings from miR-155−/− mice. Decreased blood flow recovery post-ischaemia in miR-155-deficient mice compared to controls | Angiotensin II receptor type I (AGTR1) | Pankratz et al., 2015 |