Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases

Abstract

Vascular endothelial growth factors (VEGFs) belong to the platelet-derived growth factor supergene family, and they play central roles in the regulation of angiogenesis and lymphangiogenesis. VEGF-A, the major factor for angiogenesis, binds to two tyrosine kinase (TK) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and regulates endothelial cell proliferation, migration, vascular permeability, secretion and other endothelial functions. VEGFR-2 exhibits a strong TK activity towards pro-angiogenic signals, whereas the soluble VEGFR-1 (sFlt-1) functions as an endogenous VEGF inhibitor. sFlt-1 is abnormally overexpressed in the placenta of preeclampsia patients, resulting in the major symptoms of the disease due to abnormal trapping of VEGFs. The VEGF-VEGFR system is crucial for tumour angiogenesis, and anti-VEGF-VEGFR molecules are now widely used in the clinical field to treat cancer patients. The efficacy of these molecules in prolonging the overall survival of patients has been established; however, some cancers do not respond well and reduced tumour sensitivity to anti-VEGF signals may occur after long-term treatment. The molecular basis of tumour refractoriness should be determined to improve anti-angiogenic therapy.

Fig. 1

The VEGF-VEGFR system and its involvement in various physiological and pathological processes. VEGF-A, particularly VEGF165, plays a central role in angiogenesis. VEGFxxxb has recently been reported to act as a natural antagonist to the VEGF-A. Three receptors and one soluble form of the VEGFR family members are highly conserved in most vertebrates, except for fish. Major pro-angiogenic signals are generated from VEGFR-2, whereas sFlt-1 maintains physiological corneal avascularity and induces several symptoms in PE. VEGFR-1 is expressed not only in endothelial cells but also in monocytes/macrophages and stimulates angiogenesis, inflammation and the malignant phenotypes of cancer. Nrp: co-receptors for VEGFs such as VEGF-A₁₆₅, increasing the affinity between VEGF and its receptors, and the intracellular signalling. VEGFxxxb: an alternatively processed variant form of VEGF-A and suggested to be an endogenous competitor against VEGF-A.

Fig. 2

A hypothetical model of tumour responses to anti-angiogenic therapy. The VEGF-VEGFR system plays crucial roles in tumour angiogenesis. Therefore, anti-angiogenic therapy targeting VEGF signals efficiently suppresses cancer progression. However, during therapy, tumour cells may be subjected to hypoxia and/or low nutrient stresses for extended periods, and some of the cells may acquire epigenetic modifications and resistance to these stresses, resulting in a higher cell migration as well as an increased survival signal.