vascular endothelial growth factor

vascular endothelial growth factor. It is a crucial signaling protein involved in the formation of new blood vessels, a process known as angiogenesis. First isolated in the late 1980s by teams led by Napoleone Ferrara at Genentech, it is essential for normal embryonic development and wound healing. Its dysregulation is a hallmark of numerous pathological conditions, including cancer, age-related macular degeneration, and diabetic retinopathy.

Structure and isoforms

The gene encoding this factor is located on chromosome 6 in humans and undergoes alternative splicing to produce several major protein isoforms. These isoforms, designated by their amino acid count, include VEGF121, VEGF165, VEGF189, and VEGF206. The VEGF165 isoform is the most abundant and biologically potent in most tissues. The structure is characterized by a conserved cysteine knot motif, similar to that found in platelet-derived growth factor. Research from institutions like the University of California, San Francisco has detailed how heparin sulfate proteoglycan binding differs among the isoforms, affecting their distribution and activity.

Function and mechanism

Its primary function is to stimulate angiogenesis and increase vascular permeability. It exerts its effects by binding to specific tyrosine kinase receptors, primarily VEGFR-1 and VEGFR-2, on the surface of endothelial cells. The binding to VEGFR-2 is considered the key event, triggering a cascade involving the PI3K/AKT pathway and the MAPK/ERK pathway, leading to cell proliferation, survival, and migration. It also plays a role in vasodilation by inducing the production of nitric oxide and is involved in hematopoiesis and bone marrow mobilization of endothelial progenitor cells. Pioneering work by scientists like Judah Folkman established the foundational importance of this signaling axis in vascular biology.

Role in disease

Overexpression is a key driver of pathological angiogenesis in solid tumors, as famously hypothesized by Judah Folkman. It enables tumor growth and metastasis by providing a blood supply, a concept central to oncology. In the eye, it is implicated in neovascularization in age-related macular degeneration and diabetic retinopathy, leading to vision loss. Elevated levels are also associated with rheumatoid arthritis, psoriasis, and atherosclerosis. Conversely, insufficient signaling is linked to preeclampsia and impaired wound healing in conditions like diabetes mellitus.

Clinical significance

It is a major therapeutic target. The development of bevacizumab by Genentech (marketed as Avastin) was a landmark, being a monoclonal antibody that inhibits its activity for treating colorectal cancer, non-small cell lung carcinoma, and others. Other agents include ranibizumab (Lucentis) and aflibercept (Eylea) for ocular diseases. These therapies are also used for metastatic breast cancer and glioblastoma. Measurement of its levels is used as a prognostic biomarker in cancers like renal cell carcinoma and as a predictive marker for anti-VEGF therapy response. Research from the National Cancer Institute continues to explore resistance mechanisms to these treatments.

Regulation

Its expression is tightly controlled by hypoxia, primarily through the hypoxia-inducible factor (HIF-1α) pathway, a discovery advanced by researchers like Gregg Semenza. Other inducters include growth factors like epidermal growth factor and platelet-derived growth factor, cytokines such as interleukin-1, and oncogenes like Ras. Its production is suppressed by tumor suppressor genes like p53 and by anti-angiogenic factors including thrombospondin-1. Regulation also occurs at the post-translational modification level via proteolytic cleavage, which can release matrix-bound isoforms. Environmental factors like shear stress from blood flow also modulate its expression in endothelial cells.

Category:Proteins Category:Angiogenesis Category:Growth factors