Glycometabolic Regulation of Angiogenesis: Mechanisms and Therapeutic Strategies
Abstract
1. Introduction
2. The Main Processes of Angiogenesis and Related Signaling Molecules
2.1. The Process of Angiogenesis
Key Regulators and Signaling Pathways | Cellular Origins | Primary Functions | Antagonistic Proteins/Mechanisms | References |
---|---|---|---|---|
VEGF | Macrophages, endothelial cells, tumor cells, etc. | (1) Promote endothelial cell proliferation and filopodia extension (2) Promote extracellular matrix degradation and chemotaxis | The sFlt-1 (soluble VEGF receptor), bevacizumab (anti-VEGF mAb), VEGF-Trap (recombinant fusion protein) | [25] |
bFGF | Fibroblasts, endothelial cells, etc. | (1) Promote the growth and differentiation of new cells on the wound surface (2) Induce the subcutaneous microvessel formation and improve the wound microcirculation | Heparanase, suramin (naphthaline polysulfonate), anti-FGF antibody | [26] |
HGF | Interstitial cells, hepatic stellate cells, etc. | (1) Promote endothelial cell migration and proliferation (2) Stimulate the secretion of vasculocepoetin (3) Activation of angiogenic signals through the MAPK/PI3K pathway | NK4 (HGF antagonistic protein), SU11274 (c-Met inhibitor), anti-HGF antibody (Ficlatuzumab) | [27,28] |
HIF-1 | Various cells under hypoxic conditions | (1) Regulation of the cell cycle and DNA replication (2) Proproangiogenic chemokines and receptors (3) Transcriptional activation of VEGF and other angiogenic genes | PHD 2 (through oxygen-dependent degradation), HIF-1α inhibitors (PX-478, etc.) | [29,30] |
KLFs | Endothelial cells, smooth muscle cells, etc. | (1) Regulation of endothelial cell migration and proliferation (2) Regulation of the endothelial cell metabolic pathway to promote angiogenesis | MiR-92a (by targeting KLF 2/4), KLF inhibitor (CRISPR knockout technique) | [30,31,32] |
ANG-TIE signaling pathway | Endothelial cells, pericytes, etc. | (1) Promote the proliferation and differentiation of endothelial cells (2) Enhance the cell junctions and the actin cytoskeleton to maintain vascular stability | Angiopoietin inhibitor (AMG-386), TIE2 neutralizing antibodies | [22] |
NOTCH-Dll 4 signaling pathway | Endothelial cells, hematopoietic stem cells, etc. | (1) Guide endothelial cell differentiation (2) Increase in VEGF receptor expression in the immature vascular plexus | γ-Secretase inhibitor (DAPT), anti-DLL4 antibody (Demcizumab) | [33,34,35] |
Wnt/β-catenin signaling pathway | Endothelial cells, stem cells, etc. | (1) Regulation of endothelial cell proliferation and migration (2) Regulated vascular morphogenesis in coordination with the Notch pathway (3) Induced VEGF and other factors to indirectly affect angiogenesis | DKK 1 (Wnt inhibitor), ICG-001 (β-catenin inhibitor), AXIN (scaffold protein regulates β-catenin degradation) | [36,37] |
Angiostatin | Proteolytic fragment of plasminogen | (1) Inhibition of the proliferation and migration of vascular endothelial cells (2) Block the pro-angiogenic effects of VEGF and FGF | Binding to endothelial cell surface ATP synthase, interfering with energy metabolism | [38,39] |
Endostatin | The C-terminal fragment of collagen XVIII | (1) Inhibition of endothelial cell proliferation, migration, and survival (2) Induce endothelial cell apoptosis |
Combining endothelial cell surface integrins (α5β1) and VEGFR2 to block the signaling pathway.
Inhibition of the Wnt/β-catenin pathway | [40] |
Platelet-reactive protein-1 | Platelets, endothelial cells, and fibroblasts | (1) Direct inhibition of endothelial cell migration and angiogenesis (2) Activate the potential form of TGF-β, which indirectly regulates angiogenesis | Binding to the CD36 receptor to induce apoptotic signals (e.g., caspase-3 activation); antagonizing VEGF and FGF | [41] |
Platelet factor 4 | Platelet α particles | (1) Antagonize the pro-angiogenic effects of VEGF and FGF (2) Inhibition of endothelial cell proliferation and migration | Binding heparin-like molecules, blocking growth factor binding to the receptor | [41,42] |
2.2. Angiogenesis and Vasculolysis Balance
3. Glucose Metabolism in Angiogenesis
3.1. Glycolysis Is a Primary Metabolic Pathway That Regulates Angiogenesis
3.2. GLUTs
3.3. HK2
3.4. PFKFB3
3.5. PKM2
3.6. LDHA
3.7. Other Roles of Glucose Metabolism in Angiogenesis
4. Therapeutic Strategies Targeting Angiogenesis
4.1. Therapeutic Angiogenesis
Therapeutic Method | Mechanism of Action | Superiority | Inferior Strength or Position | Clinical Stage/Representative Studies | Reference |
---|---|---|---|---|---|
Angioplasty, bypass surgery | Mechanical expansion of the narrow vessel or establishment of bypass channels to restore blood flow | (1) Significant efficacy (postoperative blood flow recovery rate > 80%) (2) Fast recovery (3 days) | (1) Only for large vessel lesions (2) Postoperative restenosis rate (20–30%) (3) It is not suitable for diffuse microvascular lesions | Clinical routine application Ultrasound guidance optimization (improve precision and reduce complications) | [98] |
Proangiogenic factor therapy | Neovascularization was stimulated by factors such as VE GF and bF GF | (1) Minimally invasive (local injection/gene delivery) (2) Inoperable microvascular lesions (such as Buerger’s disease) | (1) High cost (single session > USD 5000) (2) Susceptibility (continuous administration requirements) (3) Risk of excessive vascular proliferation (edema, tumor) | Clinical Phase II trial Synthetic mRNA-VE GF (improved collateral circulation in 74% of patients) | [93,99,100] |
Medication | Multi-target regulation (anti-inflammatory, pro-angiogenic, improved metabolism) | (1) Systemic action (covering the extensive ischemic area) (2) Easy use for oral/intravenous administration | (1) Poor targeting (systemic side effects) (2) Low delivery efficiency (<10% to the target tissue) (3) Long-term medication is required (low compliance) | Preclinical/early-stage clinical setting Nanoparticle delivery system (improves targeting) Exosomal drug loading | [97,101] |
Stem-cell/exosome therapy | Promote angiogenesis and tissue repair through paracrine factors (e. g., exosomal miRNA) | (1) Noninvasive cell repair (2) Regulation of the immune microenvironment (3) Long-acting effect (a single injection effect lasts for 4 weeks) | (1) Difficulties in standardization (high heterogeneity) (2) Potential tumorigenicity (3) High storage and transportation costs | Clinical Phase I/II trial Umbilical cord mesenchymal stem cell exosomes (60% increase in wound healing rate) | [102,103,104,105,106] |
Ultrasound targeted therapy | Low-frequency ultrasound combined with microbubbles enhances drug penetration or directly induced vasodilation | (1) Non-invasive (2) Collaborative drug therapy (3–5 times higher efficiency) | (1) High equipment dependence (2) Long-term safety is waiting to be verified (3) Limited effect on deep organization | Clinical exploration stage VE GF gene (40% increase in blood flow recovery in animal model) | [72] |
Platelet-rich blood plasma (PRP) therapy | Improving the immune environment of ischemic tissue by stimulating endothelial cell proliferation and migration with high concentrations of growth factors | Reduces immunogenicity (avoid the problem of immune response in traditional gene therapy) Can cooperate with pro-angiogenic factors | The cost is higher The PRP preparation process is complicated Long-term safety is to be verified | Preclinical/early-stage clinical setting Cord blood-derived PRP gel (reducing wound area by 80% within 14 days) | [26,107,108] |
4.2. New Strategies for Targeted Metabolism
5. Discussion
Author Contributions
Funding
Conflicts of Interest
References
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Yao, Z.; Li, J.; Yu, J.; Cheng, Y.; Fang, C.; Chen, X.; Chen, X.; Wang, Y.; Gao, D.; Lin, F. Glycometabolic Regulation of Angiogenesis: Mechanisms and Therapeutic Strategies. Int. J. Mol. Sci. 2025, 26, 2386. https://doi.org/10.3390/ijms26062386
Yao Z, Li J, Yu J, Cheng Y, Fang C, Chen X, Chen X, Wang Y, Gao D, Lin F. Glycometabolic Regulation of Angiogenesis: Mechanisms and Therapeutic Strategies. International Journal of Molecular Sciences. 2025; 26(6):2386. https://doi.org/10.3390/ijms26062386
Chicago/Turabian StyleYao, Zhifeng, Junting Li, Jiaming Yu, Ye Cheng, Chang Fang, Xinlei Chen, Xiaoqi Chen, Yizheng Wang, Dong Gao, and Fan Lin. 2025. "Glycometabolic Regulation of Angiogenesis: Mechanisms and Therapeutic Strategies" International Journal of Molecular Sciences 26, no. 6: 2386. https://doi.org/10.3390/ijms26062386
APA StyleYao, Z., Li, J., Yu, J., Cheng, Y., Fang, C., Chen, X., Chen, X., Wang, Y., Gao, D., & Lin, F. (2025). Glycometabolic Regulation of Angiogenesis: Mechanisms and Therapeutic Strategies. International Journal of Molecular Sciences, 26(6), 2386. https://doi.org/10.3390/ijms26062386