Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease

Abstract

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.

Advances in lymphatic metastasis of non-small cell lung cancer

“…NRP-2, a membrane coreceptor, was a significant molecular regulator of VEGFR-3 activation [ 54 ]. Transforming growth factor-β (TGF-β) signaling preferentially increased the abundance of NRP-2b, enhancing cellular migration, invasion, and tumorsphere formation in NSCLC [ 55 ].…”

“…Crosstalk between cancer cells and types of stromal cells in tumor tissue may lead to a specific metastasis microenvironment while contributing to LNM [ 87 ]. VEGF-C is a strong chemoattractant for macrophages and other inflammatory cells, which generate VEGF-C and influence the TME [ 54 ]. Tumor cells secrete other paracrine signaling molecules that function in parallel to VEGFR-3 to facilitate the recruitment of LVs.…”

New targets of nascent lymphatic vessels in ocular diseases

“…VEGF-C/-D is predominantly expressed by macrophages and corneal epithelial cells and binds to VEGFR-3 on LECs. This interaction activates intracellular signaling pathways, including PI3K-Akt and MAPK-ERK, leading to increased lymphatic proliferation, migration, and survival ( Kuonqui et al, 2023 ). VEGF-A also promotes corneal lymphangiogenesis by stimulating macrophages to secrete VEGF-C and VEGF-D (35), and other factors, such as Notch, which may indirectly influence angiogenesis by regulating the VEGF/VEGFR signaling pathway ( Zhu et al, 2021 ).…”

Establishment of a Mouse Model of Mycoplasma pneumoniae-Induced Plastic Bronchitis

“…Vascular endothelial growth factor receptor 3 (VEGFR-3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels [ 12 ]. The VEGFR-3, expressed on lymphatic endothelial surfaces, stimulates lymphangiogenesis via promoting cellular proliferation, migration, and survival mechanisms, which are mediated by the activation of the intracellular phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling cascade [ 13 , 14 , 15 ]. Immunohistochemical analysis was utilized to ascertain the expression of VEGFR-3 and delineate the activity of the PI3K/AKT/mTOR signaling cascade within the model, thereby elucidating the intricate association between plastic bronchitis and lymphatic vasculature anomalies.…”