The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus
Abstract
:1. Wnt Signaling Pathway in the Vasculature
2. Vascular Complications of Type 2 Diabetes Mellitus
3. Wnt Pathway and Microvascular Disease in Type 2 Diabetes Mellitus
3.1. Retinopathy
3.2. Diabetic Kidney Disease
3.3. Neuropathy
4. Wnt Pathway and Macrovascular Disease in Type 2 Diabetes Mellitus
4.1. Coronary Artery Disease
4.2. Cerebrovascular Disease
4.3. Peripheral Arterial Disease
5. Perspectives
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AD | Alzheimer disease |
ADR | Adriamycin nephropathy |
CAD | Coronary artery disease |
CVD | Cardiovascular disease |
CKD | Chronic kidney disease |
Dkk | Dickkopf |
CKD-MBD | CKD bone-mineral disorder syndrome |
DKD | Diabetic kidney disease |
DPN | Diabetic peripheral neuropathy |
EC | Endothelial cell |
ER | Endoplasmic reticulum |
ESRD | End-stage renal disease |
FRP | Follistatin-related protein |
Fzd | Frizzled |
FOXO | Forkhead box O |
GLP-1 | Glucagon-like peptide-1 |
IMT | Intima-media thickness |
LDL | Low-density lipoprotein |
LRP5 | LDL receptor-related protein |
MCAO | Middle cerebral artery occlusion |
mTOR | Mammalian target of rapamycin |
PAD | Peripheral arterial disease |
PAOD | Peripheral arterial occlusive disease |
PPARs | peroxisome proliferator-activated receptors |
PEDF | Pigment epithelium-derived factor |
RAS | Renin–angiotensin–aldosterone system |
ROS | Reactive oxygen species |
SCAI | Spinal cord area index |
SM | Salvia miltiorrhiza |
SMC | Smooth muscle cell |
STAT | Signal transducer and activator of transcription 3 |
TCF/LEF | T-cell factor/lymphoid enhancer factor family |
T2DM | Type 2 diabetes mellitus |
TG | Triglycerides |
VSMC | Vascular smooth muscle cell |
VEGF | Vascular endothelial growth factor |
VEGFR | Vascular endothelial growth factor receptor |
VLN | Very LDL receptor extracellular domain |
Wnt | Wingless-Int |
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Disease | Event | Component | Expression | In Vitro | In Vivo | Reference |
---|---|---|---|---|---|---|
Microvascular | Retinopathy | β-catenin | ↑ | Inflammation and angiogenesis | Retinal inflammation and vascular leakage | [26] |
LRP5/6 | ↑ | Inflammation and angiogenesis | Retinal inflammation and vascular leakage | [26] | ||
↓ | Lack of deeper retinal vessels | Significant decrease in pathological retinal neovascularization Significant decrease in retinal vascularization during development Affects blood–retinal barrier formation | [27] | |||
Dkk1 | ↑ | Inhibition of the generation of reactive oxygen species (ROS) | Mitigated retinal inflammation and blocked overexpression of proinflammatory factors such as ICAM-1 and COX-2 Reduction in retinal vascular leakage and improvement of ischemia-induced retinal neovascularization | [26] | ||
Frizzled4 | ↑ | Angiogenesis | Pathological neovascularization | [27] | ||
Dvl2 | ↓ | Impaired angiogenesis | Significant decrease in pathological retinal neovascularization | [27] | ||
Claudin-5 | ↓ | Significant suppression of endothelial cell sprouting | Suppression of pathological vascular growth and development | [27] | ||
Frizzled7 | ↑ | Inflammation, angiogenesis, and oxidative stress | Pathological neovascularization | [28] | ||
SERPINA3K | ↑ | Inhibition of connective tissue growth factor overexpression | Antioxidation Anti-inflammatory Antifibrosis | [29] | ||
VLDLR | ↑ | Anti-angiogenesis Inhibited endothelial cell proliferation, migration, and tube formation | Improvement of ocular neovascularization, | [30] | ||
Endostatin | ↑ | Impaired angiogenesis | Reduced VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment | [31] | ||
Kallistatin | ↑ | Anti-inflammation Anti-angiogenesis | Attenuation of ischemia-induced retinal neovascularization | [32] | ||
PEDF | ↑ | Anti-inflammation Anti-angiogenesis | Ameliorated retinal inflammation, vascular leakage, and neovascularization | [33] | ||
MiARN-184 | ↑ | Anti-angiogenesis | Improves inflammatory responses, vascular leakage, and neovascularization. | [34] | ||
Nephropathy | β-catenin | ↑ | Reduced mesangial cell apoptosis Podocyte dysfunction | Glomerular albuminuria and subsequent glomerular injury | [35] | |
↓ | Mesangial cells apoptosis | Increased severity of streptozotocin-induced diabetes nephritis | [35] | |||
LEF1 | ↑ | Enhanced proliferation and metastasis of renal cells | Renal cell carcinoma (RCC) | [36] | ||
LRP6 | ↓ | Mesangial cell apoptosis | Attenuated renal inflammation, reduced proteinuria, and ameliorated fibrosis | [37] | ||
Wnt4 | ↑ | Stimulation of mesenchymal-to-epithelial differentiation Podocyte dysfunction | Tubulo-interstitial fibrosis Glomerular albuminuria and subsequent glomerular injury | [35] | ||
↓ | Mesangial cell apoptosis | Kidney tissue disorganization, as well as disease development and progression | [38] | |||
Dkk1 | ↑ | Amelioration of podocyte apoptosis and viability | Restored podocyte function and decreased albuminuriaBone-mineral disorder syndrome | [35,39] | ||
TRPC6 | ↑ | Podocyte injury | Excessive calcium influx in podocytes leading to foot process effacement, podocyte apoptosis, and subsequent glomerular damage | [35] | ||
Wnt9a | ↑ | Evoking of cell communication between senescent tubular cells and interstitial fibroblasts | Tubular senescence and renal fibrosis | [40] | ||
Wnt5a | ↑ | Increased ROS production | Mesangial cell apoptosis | [41] | ||
CTGF/CCN2 | ↑ | LRP6 phosphorylation and accumulation of β-catenin | Attenuated renal inflammation, reduced proteinuria, and ameliorated fibrosis Mesangial cell apoptosis | [37] | ||
CTNNB1 | ↓ | Improved podocyte motility | Damage to the basement membrane, albuminuria, and increased susceptibility to glomerular injury | [41] | ||
Wnt6 | ↓ | Damaged tubulo-interstitium | Renal fibrosis | [42] | ||
Neuropathy | PORCN | ↓ | Slightly reduced expression of Wnt3a Significantly reduced expression of β-catenin, Dvl1, c-myc, GRP78, and MMP2 in the sciatic nerve | Decreased heat- and cold-induced hyperalgesia Increased motor nerve conduction speed Increased sensory nerve conduction speed Increased nerve blood flow Increased density of intraepidermal nerve fibers | [43] | |
Dvl | ↓ | Significantly reduced expression of β-catenin, Dvl1, c-myc, GRP78, and MMP2 in the sciatic nerve | Decreased heat- and cold-induced hyperalgesia Increased motor nerve conduction speed Increased sensory nerve conduction speed Increased nerve blood flow Increased density of intraepidermal nerve fibers | [43] | ||
β-catenin | ↓ | Significantly reduced expression of β-catenin, Dvl1, c-myc, GRP78, and MMP2 in the sciatic nerve | Decreased heat- and cold-induced hyperalgesia Increased motor nerve conduction speed Increased sensory nerve conduction speed Increased nerve blood flow Increased density of intraepidermal nerve fibers | [43] | ||
Wnt3a | ↑ | Release of brain-derived neurotrophic factor in microglial cells | Allodynia | [44] | ||
XAV939 | ↑ | - | Effective attenuation of neuropathic pain induction Drastic attenuation of the development of allodynia | [44] |
Disease | Event | Component | Expression | In Vitro | In Vivo | Reference |
---|---|---|---|---|---|---|
Macrovascular | Coronary artery disease | Scl | ↑ | Endothelial dysfunction, alteration on proliferation, and migration of vascular smooth muscle cells | Atherosclerotic process, abnormal intima-media thickness, carotid plaques, aortic calcifications, and mortality | [59,60] |
Dkk-1 | ↑ | Regulates platelet-mediated inflammation and contributes to plaque de-escalation | Ischemic stroke and cardiovascular death | [61] | ||
↑ | Endothelial activation and release of inflammatory cytokines Endothelial–mesenchymal transition in aortic endothelial cells | Onset and progression of atherosclerosis | [62] | |||
LRP6 | ↓ | LDL uptake was significantly lower in lymphoblastoid cells | Elevated plasma cholesterol and elevated plasma LDL, triglyceride, and fatty liver levels | [63] | ||
Wnt5a | ↑ | Induction of inflammatory gene expression GM-CSF, IL-1a, IL-3, IL-5, IL-6, IL-7, IL-8, CCL2, CCL8, and COX-2 in human aortic endothelial cells | Elevation of triglyceride levels, vascular insulin resistance, and endothelial dysfunction | [64] | ||
↑ | Macrophage activation | Increased recruitment of inflammatory cells and amplified inflammatory response | [65] | |||
Dkk-3 | ↓ | Increased intima-media thickness of the carotid artery | Delayed reendothelialization and aggravated neointima formation | [66] | ||
↑ | Induces differentiation of vascular progenitors and fibroblasts into smooth muscle cells | Larger and more vulnerable atherosclerotic lesions with more macrophages, fewer smooth muscle cells, and less extracellular matrix deposition | [67] | |||
TCF7L2 | ↓ | Loss of differentiation of vascular smooth muscle cells | Medial aortic hyperplasia | [68] | ||
Wnt2 | ↑ | Regulates smooth muscle cell migration | Triggers intima-media thickening | [69] | ||
LRP5 | ↓ | Activation of proinflammatory genes (interferon γ, IL15, IL18, and TNF ligand superfamily 13b). | Larger aortic atherosclerotic lesions | [70] | ||
Cerebrovascular disease | Scl | ↑ | Arterial calcification | Ischemic stroke caused by atherosclerotic stroke of large arteries or occlusion of small arteries | [71] | |
Dkk1 | ↑ | Biomarker for the presence of coronary atherosclerotic plaque | Carotid atherosclerosis, stable angina, and myocardial infarction Poor prognosis 1 year after ischemic stroke | [72] | ||
miR-150-5p | ↑ | Regulates the Wnt signaling pathway and participates in cell proliferation and apoptosis by downregulating p53 | Inhibition of cell proliferation, colony formation, and tumor growth | [73] | ||
↓ | CD133− cells acquire a stem-cell-like phenotype | >Glioma | [74] | |||
β-catenin | ↑ | Key regulators for cadherin-mediated cell–cell adhesion | Glioma Higher degree of malignancy of the tumor | [74] | ||
Wnt1 | ↓ | Neuronal disappearance and increasing functional deficits | Oxidant stress and cerebral ischemia | [75] | ||
claudin-1 | ↓ | Neuronal damage | Increased permeability of the blood–brain barrier, petechial hemorrhage in the brain, neuronal injury, and central nervous system inflammation | [76] | ||
Claudin-3 | ↓ | Neuronal damage | Intracerebral petechial hemorrhages | [77] | ||
Wnt3a | ↑ | Alleviates neuronal apoptosis at the cellular and subcellular levels | Neuroprotection in traumatic brain injury, and ischemic stroke | [78] | ||
LRP6 | ↓ | Increased expression of inflammatory genes after middle artery occlusion | Risk of ischemic stroke, larger heart attack, and severe motor deficits | [79] | ||
Wnt5 | ↑ | Enhanced endothelial activation type 1 inflammatory mediator to promote endothelial activation type 2 | Brain aging Inflamed atheroma plaques | [80] | ||
miRNA-148b | ↓ | Attenuates neural stem-cell proliferation and differentiation | Reduces ischemic injury and improves neurological function | [81] | ||
Peripheral arterial disease | Wnt5a | ↑ | Endothelial dysfunction | Increased risk of peripheral arterial occlusive disease, as well as metabolic and cardiovascular disorders | [82] | |
Sfrp5 | ↓ | Inhibition of cardiac fibroblast proliferation and migration Inflammation and myocardial injury | ST-segment elevation myocardial infarction, metabolic syndrome, and increased risk of peripheral arterial occlusive disease | [82] | ||
CTHRC1 | ↑ | Synovial hyperplasia, contributes to the inflammatory microenvironment, and promotes pannus invasion through increased motility and invasion of synoviocytes | Increased risk of systemic lupus erythematosus, development of rheumatoid arthritis, and severity of the disease | [83] | ||
ALKBH5 | ↑ | Reduced proliferation and migration and decreased viability in hypoxic cardiac microvascular endothelial cells | Impaired hypoxic tube formation, but not the normoxic cardiac microvascular endothelial cells | [84] |
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Sanabria-de la Torre, R.; García-Fontana, C.; González-Salvatierra, S.; Andújar-Vera, F.; Martínez-Heredia, L.; García-Fontana, B.; Muñoz-Torres, M. The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus. Int. J. Mol. Sci. 2022, 23, 6995. https://doi.org/10.3390/ijms23136995
Sanabria-de la Torre R, García-Fontana C, González-Salvatierra S, Andújar-Vera F, Martínez-Heredia L, García-Fontana B, Muñoz-Torres M. The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus. International Journal of Molecular Sciences. 2022; 23(13):6995. https://doi.org/10.3390/ijms23136995
Chicago/Turabian StyleSanabria-de la Torre, Raquel, Cristina García-Fontana, Sheila González-Salvatierra, Francisco Andújar-Vera, Luis Martínez-Heredia, Beatriz García-Fontana, and Manuel Muñoz-Torres. 2022. "The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus" International Journal of Molecular Sciences 23, no. 13: 6995. https://doi.org/10.3390/ijms23136995
APA StyleSanabria-de la Torre, R., García-Fontana, C., González-Salvatierra, S., Andújar-Vera, F., Martínez-Heredia, L., García-Fontana, B., & Muñoz-Torres, M. (2022). The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 23(13), 6995. https://doi.org/10.3390/ijms23136995