angiogenesis blood vessel growth
Length: 837 words (2.4 double-spaced pages)
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Platelets circulate in the blood and are derived from megakaryocytic in the marrow. Like erythrocytes, they are anucleate. However, unlike erythrocytes, they contain numerous intracytoplasmic granules and are the source of numerous proinflammatory mediators. In fact, they are quantitatively the greatest single source of vasoactive amines in the body. They also are a rich source of thromboxane A2. It is their activation that, in part, initiates the vascular phase of the acute inflammatory response (see Fig. 2-13 in text). To have them play this role makes imminently good sense, because they are present in large numbers throughout the circulation, i.e., some are always in close proximity to an inciting stimulus.
Vasoactive Literally translated, this adjective means that a substance has the capacity to alter the physiologic state, especially the tone and caliber, of a vessel.
Platelet-Derived Growth Factor (PDGF), a dimeric glycoprotein composed of two A and/or B chains, is the principal mitogen in serum for mesenchymal cells. Applications include culture of various cell types derived from connective tissue. It can also be used to study chemotaxis, wound healing, and bone repair. Another member of the PDGF family is the Vascular Endothelial Growth Factor (VEGF) with endothelial cell-specific activities (e.g., angiogenic and mitogenic factor).
Platelet-derived growth factor (PDGF) [1-3 reviews], a factor released from platelets upon clotting, is responsible for stimulating the proliferation of fibroblasts in vitro [4-6]. PDGF is also produced by a number of cell types besides platelets and is mitogen for vascular smooth muscle cells, bone cells, cartilage cells, connective tissue cells and some blood cells [7-9]. PDGF is stored in platelet alpha granules and released upon platelet activation. PDGFs are disulfide-linked dimers. The subunits of the PDGF dimers are homologous polypeptides designated PDGF-A and PDGF-B chains. Natural PDGFs can exist either as homodimers (PDGF-AA, PDGF-BB) or heterodimers (PDGF-AB). Two splice variants exist for the A-chain (211AA for the long isoform, 196AA for the most abundant short isoform), and C-terminal proteolytic processing apparently occurs for the B-chain (and possibly the A-chain) [10-12]. A-chain long isoform and B-chain contain a cell retention signal at the C-term end, which must be removed in order to release a freely circulating PDGF [13-16].
Two distinct human PDGF receptor transmembrane binding proteins have been identified [17,18].
PDGFR-alpha binds each of the three forms of PDGF dimers with high affinity. PDGFR-beta binds both PDGF-BB and PDGF-AB but has no reported binding to PDGF-AA [3,19,20]. PDGF binding activates intracellular tyrosine kinase, leading to autophosphorylation of the cytoplasmic domain of PDGFR, as well as phosphorylation of other intracellular substrates .[19,20]
Because there are differences between cells relative to the amounts of alpha- and beta-receptors that they express, and because of the variability in PDGF isomer binding to receptors, PDGF is involved in many biological activities, including hyperplasia, chemotaxis, embryonic neuron fiber development, and respiratory tubule epithelial cells development. PDGF binding has been linked to upregulation of ICAM-1 in vascular smooth muscle cells , transient induction of T cell IL-2 secretion , down-regulation of IL-4 and IFN-gamma production  and modulation of thrombospondin expression and secretion .
PDGF being a potent mitogen for connective tissue cells, it is implicated in cancer-driven angiogenesis .
Vigorous blood vessels that grow rapidly are the signs of a strong, healthy body, right? Wrong of course a properly functioning circulatory system is vital to good health, but excessive angiogenesis blood vessel growth is not. One example of that fact is the eye condition known as retinopathy. This disease occurs when blood vessels in the retina begin to grow at an unusually rapid rate, branching out into the clear fluids that fill the middle part of the eye. The vessels often hemorrhage resulting in scar tissue that reduces the amount of light that reaches the retina. Retinopathy is often associated with diabetes, and afflicts about 40% of those who have had that disease for more that fifteen years.
Consequently, finding the cause of the rapid growth of blood vessels was an important medical question. A group of compounds, the vascular endothelial group factor (VEGF) family, has been shown to induce blood vessel growth. This finding enabled scientist to begin the search for a substance capable of blocking these factors and inhibiting excessive blood vessel growth in conditions such as retinopathy.
Clinical trials were begun in early 2000 on squalamine , and antiangiogenic chemical classified as an aminosterol. Initial results showed squalamine capable of reducing abnormal blood vessel growth characteristic of retinopathy. In the future, squalamine may prove useful in preventing retinopathy and other eye afflictions.
Questions and Problems
1) Considerable research has been done in recent years on the identification of other types of growth factors. Select a growth factor and prepare a brief report summarizing its function
2) What other applications can you think of or find out about for a compound that would block blood vessel growth?