Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.

The pathogenesis of atherosclerosis: a perspective for the 1990s

Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis

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

Biologic basis for interleukin-1 in disease

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.

The heparin-binding (fibroblast) growth factor family of proteins.

Several of the endothelial cell polypeptide mitogens that have been described probably play a role in blood vessel homeostasis. Two overlapping complementary DNA clones encoding human endothelial cell growth factor (ECGF) were isolated from a human brain stem complementary DNA library. Southern blot analysis suggested that there is a single copy of the ECGF gene and that it maps to human chromosome 5 at bands 5q31.3 to 33.2 A 4.8-kilobase messenger RNA was present in human brain stem messenger RNA. The complete amino acid sequence of human ECGF was deduced from the nucleic acid sequence of these clones; it encompasses all the well-characterized acidic endothelial cell polypeptide mitogens described by several laboratories. The ECGF-encoding open reading frame is flanked by translation stop codons and provides no signal peptide or internal hydrophobic domain for the secretion of ECGF. This property is shared by human interleukin-1, which is approximately 30 percent homologous to ECGF.

https://science.sciencemag.org/content/sci/233/4763/541.full.pdf

Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization

Cyclooxygenase is an immediate-early gene induced by interleukin-1 in human endothelial cells.

The fibroblast growth factors are a family of structurally related polypeptides that are mitogenic for a broad range of cell types as well as mediators of a wide spectrum of developmental and pathophysiological processes in vivo and in vitro. The fibroblast growth factor family presently consists of nine distinct members. Indeed, the FGF prototypes FGF-1 (acidic) and FGF-2 (basic) are well described as modifiers of angiogenesis. The absence of a signal sequence to direct their secretion and their ability to traffic to the nucleus are unique structural features that may be relevant to the regulation of their activities. The FGF receptor family consists of four transmembrane receptor tyrosine kinases. Each of these receptors give rise to multiple isoforms as a result of alternative splicing of their mRNAs. The significance of these multiple isoforms is not fully understood; however it is known that alternative splicing in the extracellular domain of these receptors results in altered ligand binding specificities. In addition, alternative splicing in the cytoplasmic domain results in isoforms with increased oncogenic potential. This review will describe recent insights into the pathways used for the regulation of FGF secretion and cellular trafficking as well as signaling by FGFRs.

Thomas Maciag

Papers

The heparin-binding (fibroblast) growth factor family of proteins.

Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization

Cyclooxygenase is an immediate-early gene induced by interleukin-1 in human endothelial cells.

Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction.

Induction of cyclooxygenase-2 by interleukin-1 alpha. Evidence for post-transcriptional regulation.