Table 1 Preclinical studies assessing the effect of intercellular communications that EVs mediate in vascular diseases

Ischemic Stroke (IS)

MiR-98

Platelet-activating factor receptor

Neuron

Microglia

Attenuate neuronal death after IS

[39]

Transmembrane tumor necrosis factor

-

Regenerative microglia

Oligodendrocyte precursor cell (OPC)

Promote the OPC maturation and ameliorate neurological function after IS

[40]

MiR-23a-5p

OLIG3-oligodendrocyte transcription factor 3

M2 microglia

OPC

Promote white matter repair and functional recovery after IS

[41]

MiR-124

Signal transducer and activator of transcription 3

M2 microglial

Astrocyte

Attenuate glial scar formation and promote recovery after IS

[42]

-

-

Astrocyte

Neuron

Promote axonal growth and neuronal survival after IS

[44]

-

-

Activated astrocyte

Neuron

Regulate axonal growth after ischemia

[45]

MiR-25-3p

p53 pathway

Mesenchymal stem cell (MSC)

Neuron

Inhibit autophagy and have neuroprotective effects

[46]

MiR-125b-5p

Toll-like receptor 4 (TLR4) and nuclear transcription factor-kappaB (NF-κB) signaling

MSC

Astrocyte

Attenuate BBB integrity disruption induced by tPA and alleviate hemorrhage

[47]

TGF-β, Smad2, and Smad4

TGF-β/Smad signaling pathway

Embryonic stem cell (ESC)

Regulatory T cell

Alleviate neuroinflammation and promote long-term neurological recovery after IS

[48]

Intracerebral Hemorrhage (ICH)

-

-

Multipotent mesenchymal stromal cell

-

Promote neurogenesis and angiogenesis and improve functional recovery after ICH

[50]

MiR-23b

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and PTEN/Nrf2 pathway

Bone marrow mesenchymal stem cell (BMSC)

Microglia/macrophage

Exhibit antioxidant effects and promote neurologic function recovery after ICH

[51]

MiR-19b-3p

Iron regulatory protein 2

Adipose-derived stem cell (ADSC)

Neuron

Alleviate neuronal ferroptosis and improve neurological function after ICH

[52]

Signal regulatory protein α (SIRPα)- variants

CD47

MSC

Red blood cell

Accelerate hematoma clearance and ameliorate white matter injury after ICH

[53]

MiR-383-3p

Activating transcription factor 4

Activated microglia

Neuron

Promote neuron necroptosis after ICH

[54]

Vascular Dementia (VD)

MiR-154-5p

Protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2)

-

Endothelial progenitor cell (EPC)

Inhibit EPC functions and inhibit angiogenesis

[58]

MiR-132-3p

Ribosomal arginine synthetase 1 and Ras/Akt/GSK-3β pathway

MSC

Neuron

Improve synaptic dysfunction and cognitive decline in VD

[59]

MiR-17-5p, miR-18a-5p, miR-21-5p, miR-29a-3p, and let-7a-5p

Rapamycin complex 1

ESC

Hippocampal neural stem cell (HNSC)

Ameliorate senescence-related neurogenesis dysfunction and cognitive impairment in VD

[61]

MIAT

MiR-34b-5p/CALB1 axis

HNSC

Hippocampal neuronal cell

Improve cognitive disorders in VD

[62]

Cerebral Small Vascular Disease (CSVD)

-

-

MSC

Microglia

Attenuate inflammation in CSVD

[64]

Hypertension

MiR-320d/423-5p

-

Endothelial cell (EC)

Subendothelial smooth muscle cell (SMC)

Cause arterial remodeling in hypertension

[70]

MiR-483-3p

Angiotensin-converting enzyme I (ACE I), CTGF, TGF-β

EC

SMC

Inhibit endothelial dysfunction and exert protective effects on EC function during the onset of hypertension

[71]

ACE

-

Adventitial fibroblast

Vascular smooth muscle cell (VSMC)

Cause VSMC proliferation and vascular remodeling and hypertension

[72]

MiR-155-5p

ACE

Adventitial fibroblast

VSMC

Attenuate VSMC proliferation and vascular remodeling in hypertension

[73]

MiR-135a-5p

Fibronectin type III domain containing 5 (FNDC5)

Adventitial fibroblast

VSMC

Promote VSMC proliferation in hypertension

[74]

Atherosclerosis

MiR-92a

Krüppel-like factor 4 (KLF4)

EC

Macrophage

Cause atherosclerotic lesion formation in atherosclerosis

[78]

-

-

Monocyte/platelet

EC

Trigger differential activation of human atherosclerotic plaque in atherosclerosis

[79]

MiR-221

N-acetyltransferase-1

BMSC

SMC

Inhibit atherosclerotic plaque formation against atherosclerosis

[80]

MiR-146a

Src signal pathway

MSC

Senescent EC

Mitigate EC senescence and stimulate angiogenesis during atherosclerosis

[81]

MiR-27b-3p

Peroxisome proliferator-activated receptor α

Visceral adipocyte

EC

Promote endothelial inflammation and facilitate atherogenesis in atherosclerosis

[82]

MiR-155

BCL2, MCL1, TIMP3, BCL6

Nicotine-stimulated monocyte

EC

Promote plaque formation and trigger vascular endothelial injury in atherosclerosis

[83]

MiR-21-3p

PTEN

Nicotine-stimulated macrophage

VSMC

Increase VSMC migration and proliferation and accelerate atherosclerosis development

[84]

Acute Mycardial Infarction (AMI)

-

C-X-C chemokine receptor type 4

Infarcted cardiomyocyte

Bone marrow monocyte

Promote cardiac repair after AMI

[86]

CircUbe3a

MiR-138-5p/RhoC axis

M2 macrophage

Cardiac fibroblast

Exacerbate myocardial fibrosis after AMI

[87]

MiR-155

RAC1, RAK2, Sirt1, Enos, and AMPKa2

M1 macrophages

EC

Inhibit angiogenesis and aggravate heart injury after AMI

[88]

MiR-125b-5p

-

MSC

Cardiomyocyte

Inhibit autophagic after AMI

[90]

MiR-486-5p

Matrix metalloproteinase 19

Hypoxia-preconditioned MSC

Cardiac fibroblast

Promote angiogenesis after AMI

[91]

-

Foxo3

-

Regulatory T cell

Inhibit cardiac inflammation and promote cardiac repair after AMI

[92]

Myocardial Ischemia–Reperfusion Injury (MIRI)

Linc-ROR

MiR-145-5p

Cardiomyocyte

Cardiac microvascular endothelial cell (CMEC)

Increase the survival of CMECs and CMs and attenuate MIRI injury

[95]

Cardioprotective proteins

-

EC

Cardiomyocyte

Attenuate cardiac injury after MIRI

[96]

MiR-24-3p

CCR2

KLF2-overexpressing EC

Monocyte

Inhibit monocyte recruitment and attenuate MIRI

[97]

MiR-130b-3p

AMPKα1/α2, Birc6, and Ucp3

Diabetic adipocytes

Cardiomyocyte

Induce proapoptotic/cardiac harmful effects and exacerbate MIRI

[98]

Damaged mitochondria

-

Energetically stressed adipocyte

Cardiomyocyte

Protect cardiomyocytes against oxidative stress after MIRI

[99]

MiR-210

Ephrin A, protein tyrosine phosphatase 1B, and death-associated protein kinase 1

ADSC

EC and cardiomyocyte

Promote angiogenesis and inhibit apoptosis after MIRI

[100]

Heart Failure (HF)

MiR-378

Mitogen-activated protein kinase kinase 6

Cardiomyocytes under the overloaded condition

Cardiac fibroblasts

Inhibit excessive fibrosis in HF

[102]

MiR-21-5p

PTEN/Akt signaling pathway

Cardiac stromal cell

Cardiomyocyte

Enhance angiogenesis and cardiomyocyte survival in HF

[103]

-

MiR-200b

Human trophoblast stem cell

-

Have antiapoptotic and anti-inflammatory effects and attenuate doxorubicin-induced cardiac injury in HF

[105]

MiR-100-5p

NADPH oxidase 4

MSC

Cardiomyocyte

Suppress oxidative stress and play cardioprotective roles in HF

[101]

-

-

ESC

Macrophage

Attenuate pyroptosis and cardiac remodeling induced by Doxorubicin

[106]

Mitochondrial transcription factor A and mtDNA

-

MSC

-

Mitigate mitochondrial injury and inflammation in AKI

[161]

VEGF-A

Vascular endothelial growth factor receptor (VEGFR)

Tubular epithelial cell (TEC)

-

Promote angiogenesis after AKI

[162]

Diabetic Nephropathy (DN)

Chemokine ligand 7

Rapamycin complex 1 pathway

platelet

Glomerular endothelial cell

Exacerbate glomerular endothelial damage and promote the progression of DN

[107]

MiR-19b-3p

Suppressor of cytokine signaling 1

TEC

Macrophage

Drive the development of tubulointerstitial inflammation in DN

[108]

Leucine-rich α-2-glycoprotein 1

TGF-β R1

TEC

Macrophage

Promote inflammation and induce macrophages to secret EVs in DN

[109]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Death receptor 5 (DR5)

Macrophage

TEC

Induce TEC apoptosis and promote DN

[109]

MiR-199a-5p

Klotho

TEC

Macrophage

Stimulate M1 polarization and accelerate DN

[110]

MiR-93-5p

TLR4

Macrophage

Podocyte

Alleviate podocyte apoptosis and inhibit DN development

[111]

-

mTOR

MSC

-

Suppress autophagy and alleviate DN

[112]

MiR-486

Smad1/mTOR signaling pathway

ADSC

Podocyte

Promote autophagy flux, inhibit apoptosis, and ameliorate DN

[113]

14–3-3 ζ

Yes-associated protein

MSC

Podocyte

Promote autophagy and prevent DN

[114]

Diabetic Retinopathy (DR)

MiR-9-3p

Sphingosine-1-phosphate receptor 1

Retinal Muller cell

Retinal endothelial cell (REC)

Promote abnormal angiogenesis and aggravate DR

[115]

CircEhmt1

NFIA/NLRP3 pathway

Pericyte

Retinal microvascular endothelial cell (RMEC)

Improve microvascular dysfunction and ameliorate DR

[116]

MiR-30c-5p

Phospholipase C gamma 1

MSC

REC

Inhibit inflammation in DR

[117]

Neuronal precursor cell-expressed developmentally downregulated 4

PTEN

MSC

Retinal pigment epithelium cell

Inhibit apoptosis and oxidative damage and prevent DR development

[118]

MiR-192

Integrin alpha 1

MSC

-

Alleviate inflammation and angiogenesis in DR

[119]

MiR-18b

Mitogen-activated protein kinase 1

MSC

RMEC

Inhibit inflammation and apoptotic in DR

[120]

Diabetic Cardiomyopathy (DCM)

MiR-326-3p

Rictor

Senescent adipocyte

Cardiomyocyte

Cause mitochondrial dysfunction and cardiac diastolic dysfunction in DCM

[123]

Mst1

Daxx

CMEC

Cardiomyocyte

Inhibit autophagy, promote apoptosis, and alleviate DCM

[124]

MiR-499, miR-133a, and miR-133b

-

Cardiomyocyte

Cardiomyocyte

Inhibit autophagy and oxidative stress and attenuate DCM

[125]

-

-

Cardiac parasympathetic neuron

Cardiac fibroblast

Inhibit apoptosis and DCM progression

[126]

TGF-β1 mRNA

-

CMEC

Cardiac fibroblast

Promote myocardial fibrosis in DCM

[127]

Diabetic Foot Ulcers (DFU)

Nuclear factor-erythroid factor 2 (Nrf2)

-

ADSC

EPC

Promote wound healing in DFU

[128]

Linc00511

Progestin and adipoQ receptor 3

ADSC

EPC

Promote angiogenesis and attenuate DFU

[129]

Mmu_circ_0001052

MiR-106a-5p

ADSC

EC

Promote angiogenesis and wound healing and attenuate DFU

[130]

LncRNA H19

MiR-152-3p

MSC

Fibroblast

Inhibit apoptosis and inflammation and ameliorate wound ulcers in DFU

[131]

MiR-106-5p

Extracellular signal-regulated kinase 1/2

EC

Fibroblast

Activate autophagy and inhibit wound healing in DFU

[132]

LINC01435

YY1

Epidermal cell

EC

Delay the wound healing process of DFU

[133]

Hemangioma

MiR-187-3p

Notch signaling

MSC

Hemangioma stem cell (HemSC)

Suppress HemSC proliferation in hemangioma

[134]

MiR-27a-3p

Dickkopf-related protein 2

Tumor-associated macrophage

HemSC

Suppress propranolol sensitivity and decrease apoptosis in hemangioma

[135]

MiR-196b-5p

Cyclin-dependent kinase inhibitor 1B

HemSC

Hemangioma endothelial cell (HemEC)

Enhance proliferation and angiogenesis and attenuate apoptosis of HemECs in hemangioma

[136]

MiR-210

Homeobox A9

Hypoxia-induced EC

HemEC

Enhance the proliferation and migration of HemECs and inhibit apoptosis of HemECs in hemangioma

[137]

Hematological Malignancies

Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) messenger RNA

VEGFR

Acute myeloid leukemia (AML) cell

EC

Stimulate vascular remodeling and chemoresistance in AML

[140]

-

-

AML cell

EC

Promote angiogenesis in AML

[141]

-

-

Chronic myeloid leukemia (CML) cell

EC

Promote angiogenesis in CML

[142]

Chloride intracellular channel 1

ITGβ1

Chronic lymphocytic leukemia (CLL) cell

EC

Promote angiogenesis in CLL

[143]

-

-

Diffuse large B cell lymphoma (DLBCL) cell

EC

Promote angiogenesis in DLBCL

[144]

VEGF

VEGF/Akt signaling pathway

Lymphoma cells treated with curcumin and omacetaxine

EC

Inhibit angiogenesis in lymphoma

[145]

Other Solid Tumors

miR-25-3p

KLF2 and KLF4

CRC cell

EC

Promote angiogenesis and metastasis in CRC

[147]

Glutamine-fructose-6-phosphate aminotransferase 1

-

Bladder cancer cell

EC

Realize metabolic reprogramming and promote angiogenesis in bladder cancer

[148]

Lysyl oxidase-like 4 (LOXL4)

The FAK/Src pathway

Hepatocellular carcinoma (HCC)

EC

Promote angiogenesis, enhance invasion, and exacerbate HCC metastasis

[149]

MiR-9

Collagen type XVIII alpha 1 chain, thrombospondin 2, patched 1, and prolyl hydroxylase domain 3

Glioma cell

EC

Promote angiogenesis in glioma

[150]

MiR-9

MDK

Nasopharyngeal carcinoma cell

EC

Inhibit angiogenesis in nasopharyngeal carcinoma

[151]

MiR-522

Arachidonate lipoxygenase 15

Cancer-associated fibroblast (CAF)

Gastric cancer cell

Inhibit ferroptosis and induce chemical resistance

[152]

EGFR

PI3K/AKT and MAPK pathways

Wild EGFR non-small cell lung cancer (NSCLC) cell

Mutated EGFR NSCLC cell

Promote the resistance to osimertinib

[154]

Acute Lung Injury (ALI)

MiR-30d-5p

Suppressor of cytokine signaling 1 and Sirt1

Polymorphonuclear neutrophil

Macrophage

Induce M1 macrophage polarization and pyroptosis and aggravate ALI

[155]

mtDNA

-

MSC

Macrophage

Reduce inflammation and improve ALI

[156]

MiR-125b-5p

Keap1

ADSC

Pulmonary microvascular endothelial cell (PMVEC)

Alleviate inflammation and improve ALI

[157]

MiR-126-3p and MiR-126-5p

Phosphoinositide-3-kinase regulatory subunit 2

EPC

EC

Inhibit inflammation and microvascular dysfunction and alleviate ALI

[158, 159]

Acute Kidney Injury (AKI)

MiR-200a-3p

Keap1

MSC

TEC

Enhance mitochondrial function and improve renal function during AKI

[160]

Mitochondrial transcription factor A and mtDNA

-

MSC

-

Mitigate mitochondrial injury and inflammation in AKI

[161]

VEGFA

VEGFR

TEC

-

Promote angiogenesis after AKI

[162]