Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents “mandatory damage” in the development of microvascular complications and only “introductory damage” in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM.
Patients with T2DM usually present complications related to the deterioration of the vascular system which are classified as microvascular disease when it affects small vessels [21]. The microcirculation is a network of blood vessels <150 μm in diameter, comprising arterioles, capillaries, and venules [22]. This network is responsible for the primary function of the vascular tree and regulation of tissue perfusion for optimal exchange of gases and removal of metabolic waste products, and it may contribute to the unexplained variance in the association between T2DM and hypertension [21]. Small arterioles and capillaries also exhibit differential vascular remodeling in response to hypertension and T2DM [22]. The number of vessels perfused in the vascular bed and the arteriolar diameter determine the peripheral vascular resistance [23].
The main manifestations of the microvascular disease related to T2DM are diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy [24] (Figure 2). The mechanisms that lead to vascular damage are multiple and involve various alterations in signaling pathways, including the Wnt pathway [13,25].
Table 1 shows some components of the Wnt pathway that are altered in the microvascular diseases in T2DM patients.
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][44][45] | ||||
Dkk-1 | ↑ | Regulates platelet-mediated inflammation and contributes to plaque de-escalation | Ischemic stroke and cardiovascular death | [61][46] | ||||||
↓ | Lack of deeper retinal vessels | Significant decrease in pathological retinal neovascularization Significant decrease in retinal vascularization during development Affects blood–retinal barrier formation |
[ | |||||||
↑ | Endothelial activation and release of inflammatory cytokines Endothelial–mesenchymal transition in aortic endothelial cells |
Onset and progression of atherosclerosis | 21] | |||||||
[ | 62 | ] | [47] | 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 |
[20] | ||
LRP6 | ↓ | LDL uptake was significantly lower in lymphoblastoid cells | Elevated plasma cholesterol and elevated plasma LDL, triglyceride, and fatty liver levels | [63][48] | Frizzled4 | ↑ | Angiogenesis | Pathological neovascularization | [21] | |
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][49] | Dvl2 | ↓ | Impaired angiogenesis | Significant decrease in pathological retinal neovascularization | [21 | |
↑ | Macrophage activation | ] | ||||||||
Increased recruitment of inflammatory cells and amplified inflammatory response | [ | 65 | ][50] | Claudin-5 | ↓ | Significant suppression of endothelial cell sprouting | Suppression of pathological vascular growth and development | [21 | ||
Dkk-3 | ↓ | ] | ||||||||
Increased intima-media thickness of the carotid artery | Delayed reendothelialization and aggravated neointima formation | [ | 66 | ][51] | Frizzled7 | ↑ | Inflammation, angiogenesis, and oxidative stress | Pathological neovascularization | ||
↑ | 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][52] | [22] | ||||||
SERPINA3K | ↑ | Inhibition of connective tissue growth factor overexpression | Antioxidation Anti-inflammatory Antifibrosis |
[23] | ||||||
TCF7L2 | VLDLR | ↑ | Anti-angiogenesis Inhibited endothelial cell proliferation, migration, and tube formation |
Improvement of ocular neovascularization, | [24] | |||||
↓ | Loss of differentiation of vascular smooth muscle cells | Medial aortic hyperplasia | [ | 68][53] | ||||||
Wnt2 | ↑ | Regulates smooth muscle cell migration | Triggers intima-media thickening | [69][54] | Endostatin | ↑ | Impaired angiogenesis | |||
LRP5 | ↓ | Reduced VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment | [ | Activation of proinflammatory genes (interferon γ, IL15, IL18, and TNF ligand superfamily 13b). | Larger aortic atherosclerotic lesions25] | |||||
[ | 70 | ] | [ | 55] | Kallistatin | ↑ | Anti-inflammation | |||
Cerebrovascular disease | Anti-angiogenesis | Attenuation of ischemia-induced retinal neovascularization | [26] | |||||||
Scl | ↑ | Arterial calcification | Ischemic stroke caused by atherosclerotic stroke of large arteries or occlusion of small arteries | [ | 71][56] | PEDF | ↑ | Anti-inflammation Anti-angiogenesis |
Ameliorated retinal inflammation, vascular leakage, and neovascularization | |
Dkk1 | ↑ | Biomarker for the presence of coronary atherosclerotic plaque | Carotid atherosclerosis, stable angina, and myocardial infarction Poor prognosis 1 year after ischemic stroke | [27] | ||||||
[ | 72 | ] | [ | 57] | MiARN-184 | ↑ | Anti-angiogenesis | Improves inflammatory responses, vascular leakage, and neovascularization. | [28] | |
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][58] | Nephropathy | β-catenin | ||||
↓ | ↑ | CD133Reduced mesangial cell apoptosis Podocyte dysfunction |
Glomerular albuminuria and subsequent glomerular injury | − cells acquire a stem-cell-like phenotype | >Glioma | [74][59[29] | ||||
] | ↓ | Mesangial cells apoptosis | Increased severity of streptozotocin-induced diabetes nephritis | [29] | ||||||
β-catenin | ↑ | Key regulators for cadherin-mediated cell–cell adhesion |
Glioma Higher degree of malignancy of the tumor |
[74][59] | LEF1 | ↑ | Enhanced proliferation and metastasis of renal cells | Renal cell carcinoma (RCC) | [30] | |
Wnt1 | ↓ | Neuronal disappearance and increasing functional deficits | Oxidant stress and cerebral ischemia | [75][60] | LRP6 | ↓ | Mesangial cell apoptosis | Attenuated renal inflammation, reduced proteinuria, and ameliorated fibrosis | [31] | |
claudin-1 | ↓ | Neuronal damage | Increased permeability of the blood–brain barrier, petechial hemorrhage in the brain, neuronal injury, and central nervous system inflammation | [76][61] | Wnt4 | ↑ | Stimulation of mesenchymal-to-epithelial differentiation Podocyte dysfunction |
Tubulo-interstitial fibrosis Glomerular albuminuria and subsequent glomerular injury |
[29 | |
Claudin-3 | ↓ | ] | ||||||||
Neuronal damage | Intracerebral petechial hemorrhages | [ | 77 | ][62] | ↓ | Mesangial cell apoptosis | Kidney tissue disorganization, as well as disease development and progression | [32 | ||
Wnt3a | ↑ | ] | ||||||||
Alleviates neuronal apoptosis at the cellular and subcellular levels | Neuroprotection in traumatic brain injury, and ischemic stroke | [ | 78 | ][63] | Dkk1 | ↑ | Amelioration of podocyte apoptosis and viability | Restored podocyte function and decreased albuminuriaBone-mineral disorder syndrome | [29 | |
LRP6 | ] | [ | 33 | ] | ||||||
↓ | TRPC6 | ↑ | Podocyte injury | Excessive calcium influx in podocytes leading to foot process effacement, podocyte apoptosis, and subsequent glomerular damage | [29] | |||||
Wnt9a | ↑ | Evoking of cell communication between senescent tubular cells and interstitial fibroblasts | Tubular senescence and renal fibrosis | [34] | ||||||
Increased expression of inflammatory genes after middle artery occlusion | Risk of ischemic stroke, larger heart attack, and severe motor deficits | [ | 79 | ][64] | ||||||
Wnt5 | ↑ | Enhanced endothelial activation type 1 inflammatory mediator to promote endothelial activation type 2 | Brain aging Inflamed atheroma plaques |
[80][65] | ||||||
miRNA-148b | ↓ | Attenuates neural stem-cell proliferation and differentiation | Reduces ischemic injury and improves neurological function | [81][66 | Wnt5a | ↑ | Increased ROS production | Mesangial cell apoptosis | [35] | |
] | ||||||||||
Peripheral arterial disease | Wnt5a | ↑ | Endothelial dysfunction | Increased risk of peripheral arterial occlusive disease, as well as metabolic and cardiovascular disorders | [82][67] | CTGF/CCN2 | ↑ | LRP6 phosphorylation and accumulation of β-catenin | Attenuated renal inflammation, reduced proteinuria, and ameliorated fibrosis Mesangial cell apoptosis |
[ |
Sfrp5 | ↓ | Inhibition of cardiac fibroblast proliferation and migration Inflammation and myocardial injury | 31 | ] | ||||||
ST-segment elevation myocardial infarction, metabolic syndrome, and increased risk of peripheral arterial occlusive disease | [ | 82 | ] | [67] | CTNNB1 | ↓ | Improved podocyte motility | Damage to the basement membrane, albuminuria, and increased susceptibility to glomerular injury | [35 | |
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 | ][68] | Wnt6 | ↓ | Damaged tubulo-interstitium | |||
ALKBH5 | ↑ | Reduced proliferation and migration and decreased viability in hypoxic cardiac microvascular endothelial cells | Renal fibrosis | [36] | ||||||
Impaired hypoxic tube formation, but not the normoxic cardiac microvascular endothelial cells | [ | 84 | ] | [69] | 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 |
[37] |
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 |
[37] | ||||||
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 |
[37] | ||||||
Wnt3a | ↑ | Release of brain-derived neurotrophic factor in microglial cells | Allodynia | [38] | ||||||
XAV939 | ↑ | - | Effective attenuation of neuropathic pain induction Drastic attenuation of the development of allodynia |
[38] |
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 over expression of pro inflammatory 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 overexpresion | Anti-oxidation, anti-inflammatory, anti-fibrosis | [29] | ||
Nephropathy | 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-infflammation, anti-angiogenesis | Attenuation of ischemia-induced retinal neovascularization | [32] | ||
PEDF | ↑ | Anti-infflammation, anti-angiogenesis | Ameliorated retinal inflammation, vascular leakage and neovascularization | [33] | ||
miRNA-184 | ↑ | Anti-angiogenesis | Improved inflammatory responses, vascular leakage and neovascularization | [34] | ||
β-catenin | ↑ | Reduced mesangial cell apoptosis, Podocyte dysfunction | Glomerular albuminuria and subsequent glomerular injury | [35] | ||
↓ | Mesangian cells apoptosis | Increased severity of streptozotocin-induced diabetes nephritis | [35] | |||
LEF1 | ↑ | Enhanced proliferation and metastasis of renal cells | Renal cell carcinoma (RCC) | [36] | ||
LRP6 | ↓ | Mesangian cells apoptosis | Attenuated renal inflammation, reduced proteinuria and ameliorated fibrosis | [37] | ||
Wnt4 | ↑ | Stimulation of mesenchymal-to-epithelial differentiation, podocyte disfunction | Tubulo-intersticial fibrosis, glomerular albuminuria and subsequent glomerular injury | [35] | ||
↓ | Mesangian cells apoptosis | Kidney tissue disorganization, as well as disease development and progression | [38] | |||
Dkk1 | ↑ | Amelioration of podocyte apoptosis and viability | Restored podocyte function and decreased albuminuria, bone-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] |