VEGF Family (VEGFs and Receptors)

Overview of the VEGF Family: Functions and Members

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a highly specific factor that stimulates the growth of vascular endothelial cells, matrix degeneration, vascular endothelial cell migration, proliferation, and angiogenesis. The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PGF). VEGF-A, the most commonly studied member, promotes new blood vessel formation and increases blood vessel permeability. VEGF-B plays a role in non-neovascular tumors, while VEGF-C and VEGF-D contribute to the formation of new blood vessels and lymphatic vessels in cancer tissues. VEGF-E is also a potential factor for neovascularization, and PGF promotes neovascularization and increases vascular permeability, with significantly elevated expression observed in experimental choroidal neovascularization. Additionally, VEGF acts as a specific mitogen for vascular endothelial cells, inducing their growth in vitro and stimulating vascular proliferation in vivo, particularly in hypoxic environments. This effect is achieved through the binding of VEGF to its receptor on the endothelial cell membrane, triggering receptor autophosphorylation, activation of mitogen-activated protein kinase (MAPK), and subsequent endothelial cell proliferation.

VEGF Receptors: Roles and Functions

VEGF primarily targets vascular endothelial cells and interacts with two specific receptors present exclusively in these cells: fetal-liver kinase-1/kinase-containing Insertion region receptor (flk-1/KDR) and fms-like tyrosine kinase (flt-1). These receptors, belonging to the tyrosine kinase receptor family, exhibit distinct effects upon VEGF binding and activation. Flk-1 triggers endothelial cell division and migration upon activation, while flt-1 does not induce significant mitogenic effects. Instead, flt-1 is associated with the regulation of endothelial cell interactions and their connection to the basement membrane. As a result, these two receptor types likely work synergistically in vascular development and the regulation of vascular permeability.

VEGF-A: A Key Promoter of Angiogenesis

VEGF-A, the prototypical and vital member of the VEGF family, is a cytokine that plays a central role in promoting angiogenesis. By binding to its receptors, VEGFR-1 and VEGFR-2, VEGF-A stimulates endothelial cell proliferation, migration, and lumen formation, thereby facilitating the development of new blood vessels. This process is critical for embryonic development, tissue repair, regeneration, and also contributes to tumor growth and metastasis. VEGF-B and VEGF-C also participate in angiogenesis, particularly during embryonic development and lymphangiogenesis.

VEGF-D: Regulating the Vascular and Lymphatic Systems

VEGF-D primarily contributes to lymphatic vessel formation and expansion, exerting a significant impact on the normal functioning of the lymphatic system. PlGF, a factor associated with angiogenesis and inflammatory responses, binds to VEGFR-1, leading to endothelial cell proliferation and increased vascular permeability.

Clinical Significance of VEGF Detection in Tumor Management:

1. Early Tumor Screening: Rapid tumor growth and metastasis prompt tumor cells to produce high levels of VEGF, promoting new blood vessel formation. This stage, typically in Tis and T1 tumor stages, presents an optimal opportunity for early tumor screening, leading to improved survival rates and extended survival time for cancer patients.
2. Broad-Spectrum Tumor Screening: Any change in angiogenesis tendencies corresponds to alterations in VEGF concentration. VEGF can detect almost all solid tumors, making it an irreplaceable tool for broad-spectrum tumor screening. The figure below illustrates the coverage of VEGF across most solid tumors and certain non-solid tumors.
3. Clinical Diagnosis and Prognosis Assessment: In cases where specific tumor markers are lacking, VEGF blood detection can aid in the diagnosis of malignant tumors, such as renal cancer. Moreover, VEGF levels reflect tumor development and can be utilized to assess prognosis. Generally, higher VEGF levels indicate increased malignancy and poorer prognosis for the same malignant tumor.

Role of the VEGF Family in Regulating Angiogenesis and Its Significance in Disease Treatment

The VEGF family of growth factors plays a crucial role in modulating downstream signaling pathways that regulate endothelial cell function and blood vessel growth. These factors have significant implications in various diseases, including tumors, eye diseases, and cardiovascular conditions. As a result, the members of the VEGF family and their receptors have emerged as important targets for the development of treatments for vascular-related diseases. Several anti-VEGF drugs have been developed for tumor and eye disease treatment, demonstrating remarkable clinical efficacy.

Summary: The Impact of the VEGF Family on Physiology and Disease

In summary, the VEGF family members are key players in angiogenesis and vascular remodeling processes, holding significant importance in both normal physiological functions and the development of various diseases. Through in-depth research into the mechanisms of the VEGF family and the development of related drugs, new therapeutic strategies and opportunities are expected to emerge for the treatment of vascular-related disorders.

References:

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