Vegfd, a member of the VEGF family, is implicated in angiogenesis and lymphangiogenesis [2]. It is also crucial for the maintenance of mature dendritic trees in neurons, influencing the actin cortex and microtubule dynamics to balance dendritic structural plasticity and stabilization [3]. In zebrafish, Vegfd has been shown to have context-specific roles in both blood vessel angiogenesis and lymphangiogenesis, as well as in facial lymphatic sprouting, sometimes compensating for the loss of Vegfc [4,8]. Vegfd also regulates blood vascular development by modulating SOX18 activity [5].

In myofibroma, a novel COL4A1-Vegfd gene fusion was identified, leading to Vegfd production under the control of the COL4A1 gene promoter [1]. In lung adenocarcinoma, S-nitrosylation-mediated suppression of Vegfd expression promotes tumorigenesis [2]. In ischemic stroke in mice, Vegfd/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives neuroinflammation [6]. In the retina, Vegfd protects retinal ganglion cells and capillaries against excitotoxic injury [7]. In head and neck cancer, SIRT2 modulates Vegfd-associated lymphangiogenesis by deacetylating EPAS1 [9].

In summary, Vegfd plays essential roles in multiple biological processes such as angiogenesis, lymphangiogenesis, and neuronal dendritic stability. Studies in zebrafish and mouse models have revealed its significance in various disease conditions including myofibroma, lung adenocarcinoma, ischemic stroke, and head and neck cancer, highlighting its potential as a therapeutic target in these diseases.

References:

1. Dachy, Guillaume, Fraitag, Sylvie, Boulouadnine, Boutaina, Cordi, Sabine, Demoulin, Jean-Baptiste. 2021. Novel COL4A1-VEGFD gene fusion in myofibroma. In Journal of cellular and molecular medicine, 25, 4387-4394. doi:10.1111/jcmm.16502. https://pubmed.ncbi.nlm.nih.gov/33830670/

2. He, Qiangqiang, Qu, Meiyu, Shen, Tingyu, Zeng, Ling-Hui, Wu, Ximei. 2022. Suppression of VEGFD expression by S-nitrosylation promotes the development of lung adenocarcinoma. In Journal of experimental & clinical cancer research : CR, 41, 239. doi:10.1186/s13046-022-02453-8. https://pubmed.ncbi.nlm.nih.gov/35941690/

3. Aksan, Bahar, Kenkel, Ann-Kristin, Yan, Jing, Missirlis, Dimitris, Mauceri, Daniela. 2024. VEGFD signaling balances stability and activity-dependent structural plasticity of dendrites. In Cellular and molecular life sciences : CMLS, 81, 354. doi:10.1007/s00018-024-05357-2. https://pubmed.ncbi.nlm.nih.gov/39158743/

4. Bower, Neil I, Vogrin, Adam J, Le Guen, Ludovic, Achen, Marc G, Hogan, Benjamin M. 2017. Vegfd modulates both angiogenesis and lymphangiogenesis during zebrafish embryonic development. In Development (Cambridge, England), 144, 507-518. doi:10.1242/dev.146969. https://pubmed.ncbi.nlm.nih.gov/28087639/

5. Duong, Tam, Koltowska, Katarzyna, Pichol-Thievend, Cathy, Hogan, Benjamin M, Francois, Mathias. 2013. VEGFD regulates blood vascular development by modulating SOX18 activity. In Blood, 123, 1102-12. doi:10.1182/blood-2013-04-495432. https://pubmed.ncbi.nlm.nih.gov/24269955/

6. Wang, Shuai, Guo, Yi, Cao, Rui-Qi, Schoen, Ingmar, Zhang, Hui-Ling. 2024. VEGFD/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives neuroinflammation in mouse ischemic stroke. In Acta pharmacologica Sinica, 46, 292-307. doi:10.1038/s41401-024-01405-6. https://pubmed.ncbi.nlm.nih.gov/39478160/

7. Schlüter, Annabelle, Aksan, Bahar, Diem, Ricarda, Fairless, Richard, Mauceri, Daniela. 2019. VEGFD Protects Retinal Ganglion Cells and, consequently, Capillaries against Excitotoxic Injury. In Molecular therapy. Methods & clinical development, 17, 281-299. doi:10.1016/j.omtm.2019.12.009. https://pubmed.ncbi.nlm.nih.gov/32055648/

8. Astin, Jonathan W, Haggerty, Michael J L, Okuda, Kazuhide S, Crosier, Kathryn E, Crosier, Philip S. 2014. Vegfd can compensate for loss of Vegfc in zebrafish facial lymphatic sprouting. In Development (Cambridge, England), 141, 2680-90. doi:10.1242/dev.106591. https://pubmed.ncbi.nlm.nih.gov/24903752/

9. Hu, An, Yang, Li-Yun, Liang, Jia, Dai, Wei-Jun, Zhang, Jing-Fei. 2020. SIRT2 modulates VEGFD-associated lymphangiogenesis by deacetylating EPAS1 in human head and neck cancer. In Molecular carcinogenesis, 59, 1280-1291. doi:10.1002/mc.23256. https://pubmed.ncbi.nlm.nih.gov/32965071/