Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.

https://science.sciencemag.org/content/sci/246/4935/1306.full.pdf

Vascular endothelial growth factor is a secreted angiogenic mitogen

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

/pdf/vascular-endothelial-growth-factor-basic-science-and-17gyy6h97s.pdf

Vascular endothelial growth factor: basic science and clinical progress.

Majors topics addressed in this review on zinc physiology are ; 1) chemistry and biochemistry; 2) interface of biochemistry and physiology of zinc; 3) physiology and cell and molecular biology; 4) pathology

The biochemical basis of zinc physiology

https://www.cell.com/cell/pdf/0092-8674(91)90642-C.pdf

Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation.

Trophic factors and neuronal survival

Bovine brain-derived acidic fibroblast growth factor (aFGF) is a protein mitogen originally identified in partially purified preparations of whole brain. The protein was purified to homogeneity and shown to be a potent vascular endothelial cell mitogen in culture and angiogenic substance in vivo. The homology of aFGF to human interleukin-1 beta was inferred from partial sequence data. The complete amino acid sequence of aFGF has now been determined and observed to be similar to both basic FGF and interleukin-1's. A neuropeptide-like sequence, flanked by basic dipeptides, was observed within the aFGF sequence.

https://science.sciencemag.org/content/sci/230/4732/1385.full.pdf

Brain-Derived Acidic Fibroblast Growth Factor: Complete Amino Acid Sequence and Homologies

Pure bovine brain-derived acidic fibroblast growth factor is a very potent mitogen for vascular endothelial cells in culture and, in the presence of heparin, induces blood vessel growth in vivo. Partial amino acid sequence determinations confirm that this mitogen is a unique protein having amino acid sequence homology with human interleukin 1.

Pure brain-derived acidic fibroblast growth factor is a potent angiogenic vascular endothelial cell mitogen with sequence homology to interleukin 1.

Acidic brain fibroblast growth factor has been purified a minimum of 35,000-fold to apparent homogeneity by a combination of differential salt precipitation, ion exchange chromatography, gel filtration, isoelectric focusing, and hydrophobic chromatography on a C4 reversed-phase HPLC column. Two microheterogeneous forms of the molecule are obtained with apparent molecular masses of 16,600 and 16,800 daltons. The mitogen is highly active with half-maximal stimulation of BALB/c 3T3 fibroblasts at about 40 pg/ml in an assay using incorporation of [methyl-3H]thymidine into DNA.

Purification and characterization of acidic fibroblast growth factor from bovine brain.

Bovine brain, hypothalamus, pituitary, and retina contain potent anionic polypeptide mitogens for endothelial cells. Immunological assays using murine monoclonal antibodies against bovine endothelial cell growth factor (ECGF) and radioreceptor assays using [125I]ECGF were performed to determine the cross-reactivity of ECGF with bovine acidic pI brain-derived fibroblast growth factor (acidic FGF) and bovine eye-derived growth factor-II [EDGF-II). We observed that acidic FGF and EDGF-II are recognized by anti-ECGF monoclonal antibodies and compete with [125I] ECGF for receptor occupancy. Furthermore, the biological activity of ECGF, acidic FGF, and EDGF-II is potentiated by the glycosaminoglycan, heparin. These results argue that ECGF, acidic FGF, and EDGF-II belong to a common family of polypeptide growth factors.

/pdf/a-unique-family-of-endothelial-cell-polypeptide-mitogens-the-4xhw332kkd.pdf

A Unique Family of Endothelial Cell Polypeptide Mitogens: The Antigenic and Receptor Cross-Reactivity of Bovine Endothelial Cell Growth Factor, Brain-derived Acidic Fibroblast Growth Factor, and Eye-derived Growth Factor-II

The effect of natural protease inhibitors and a chemoattractant on tumor cell invasion were studied with the use of a new in vitro quantitative assay of tumor cell penetration of native connective tissue. Human amnion membrane denuded of its epithelium is composed of a continuous basement membrane (BM) attached to a dense avascular collagenous stroma. M5076 reticulum sarcoma cells, known to be highly invasive in vivo, were placed on the BM side of the amnion connective tissue. Tumor cells penetrating the full thickness of the connective tissue barrier were collected on the stromal side with a Millipore filter. N-Formylmethionyl-leucyl-phenylalanine (FMLP) at an optimal concentration of 10(-7) M stimulated the penetration of up to 600% more tumor cells into the connective tissue after 20 hours in comparison to the number of tumor cells spontaneously penetrating in serum-free media. Natural protease inhibitors blocked both FMLP-stimulated and spontaneous invasion. A bovine cartilage extract containing inhibitors of both serine proteinases and metalloproteinases caused a 500% decrease in invasion. Furthermore, a 500% inhibition of invasion was produced by a purified collagenase (metalloproteinase) inhibitor. In contrast, soybean trypsin inhibitor and bovine serum albumin did not significantly alter the invasion rate. The protease inhibitors were nontoxic and did not reduce tumor cell proliferation, attachment to the amnion, and the rate of tumor cell migration through Nuclepore filters. These data support the hypothesis that collagenolytic metalloproteinases play a necessary role in tumor cell invasion of native connective tissue.

Mari Rios-Candelore

Papers

Brain-Derived Acidic Fibroblast Growth Factor: Complete Amino Acid Sequence and Homologies

Pure brain-derived acidic fibroblast growth factor is a potent angiogenic vascular endothelial cell mitogen with sequence homology to interleukin 1.

Purification and characterization of acidic fibroblast growth factor from bovine brain.

A Unique Family of Endothelial Cell Polypeptide Mitogens: The Antigenic and Receptor Cross-Reactivity of Bovine Endothelial Cell Growth Factor, Brain-derived Acidic Fibroblast Growth Factor, and Eye-derived Growth Factor-II

Effect of Natural Protease Inhibitors and a Chemoattractant on Tumor Cell Invasion In Vitro