Table 2.

Components of the Wnt pathway that can be altered in the macrovascular complications of T2DM ².

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]

² Dkk: Dickkopf; LRP: LDL receptor-related protein; LDL: low-density lipoprotein; Wnt: Wingless-Int; GM-CSF: granulocyte macrophage-colony stimulating factor; IL: interleukin; CCL: collagen crosslinking; COX: cyclooxygenase; TCF: transcription factor; TNF: tumor necrosis factor; Scl: sclerostin; CD: cluster of differentiation; Sfrp: secreted Frizzled-related proteins; CTHRC: collagen triple helix; ↑: upregulation; ↓: downregulation.