Multidimensional target regulation of vascular endothelial growth factor A in articular cartilage development

Wang Zhengye; Liu Wanlin; Zhao Zhenqun

doi:10.12307/2026.720

Abstract：BACKGROUND:The health and functional maintenance of articular cartilage are hot topics in the field of orthopedics.Vascular endothelial growth factor A,as a key regulator of angiogenesis,has long been a subject of debate regarding its role in cartilage development. OBJECTIVE:To systematically summarize the multidimensional regulatory mechanisms of vascular endothelial growth factor A in articular cartilage development and its role in diseases,explore its feasibility as a therapeutic target,and analyze the current technical bottlenecks and potential breakthroughs in treatment strategies. METHODS:A comprehensive literature search was conducted in PubMed,CNKI,WanFang Data,and VIP databases(from database inception to May 2025),supplemented by manual retrieval of relevant books.High-quality studies focusing on the regulatory mechanisms of vascular endothelial growth factor A in articular cartilage development and diseases were selected.A total of 117 articles(112 in English and 5 in Chinese)were included for systematic analysis and synthesis. RESULTS AND CONCLUSION:Vascular endothelial growth factor A spatiotemporally modulates chondrocyte differentiation and metabolism via interactions with its receptors;its splice isoforms exhibit distinct roles in cartilage development and diseases;the coupling of mechanical and biochemical signals further enhances regulatory complexity.In osteoarthritis,the expression of vascular endothelial growth factor A is concentration-dependent,with low levels promoting cartilage repair and high levels exacerbating cartilage degradation.In rheumatoid arthritis,vascular endothelial growth factor A aggravates disease progression by promoting synovial angiogenesis and inflammatory cell infiltration.In developmental dysplasia of the hip,vascular endothelial growth factor A significantly promotes joint cartilage development.Vascular endothelial growth factor A shows promise for early disease intervention,but major bottlenecks remain,including inadequate spatiotemporal precision in delivery systems,off-target risks of gene editing,and the lack of molecular subtyping for personalized treatment.In conclusion,vascular endothelial growth factor A exerts complex and pleiotropic effects in articular cartilage development and disease,necessitating precise modulation for therapeutic applications.Current research faces bottlenecks in delivery system precision,gene editing safety,and the absence of personalized treatment strategies.Future work should focus on optimizing delivery systems,integrating single-cell multi-omics for personalized therapy,and exploring vascular endothelial growth factor A crosstalk with other signaling pathways.Additionally,there is an urgent need to shift the research paradigm from"single-target inhibition"to"microenvironment remodeling,"relying on interdisciplinary technical integration and precise design of preclinical models.Comprehensive efforts are required to overcome challenges and promote clinical translation,including single-cell sequencing to elucidate chondrocyte subpopulation responses,CRISPR-Cas9 screening for stage-specific regulatory elements,development of intelligent controlled-release systems,interaction models,engineered carriers,integration of multi-omics,construction of organoid models,and the use of artificial intelligence for prediction,bringing new hope for the treatment of articular cartilage-related diseases.