Pfeffer Rao and Weir Stuff Flashcards
What is vasculogenesis ?
earliest morphogenetic process of vascular development that takes place exclusively in embryonic development. Consists of differentiation of angioblasts into blood islands, which then fuse to form primitive capillary plexuses.
What is angiogenesis ?
a process by which new capillary blood vessels sprout from a preexisting blood vessel. Any developing new network of endothelial tubes (sprouting capillaries) that is not surrounded by mural cells is fragile and prone to rupture, remains susceptible to hypoxic regulation, fails to become remodeled, and is unable to sustain proper circulation; it cannot adapt to changes in physiological demands of blood supply.
What growth factor mediates angiogenesis ?
Vascular endothelial growth factor family is the major regulator of angiogenesis. Endothelial cells, tumor cells, fibroblasts and many other cells, produce VEGF.
What are the stimuli of angiogenesis ?
The major stimuli of angiogenesis are VEGF, hypoxia, PDGF, angiopoietins and histamine.
What does VEGF do ?
Direct actions of VEGF include:
- Stimulation of endothelial mitogenesis
- Promotion of endothelial survival by an Akt-dependent pathway
- Control of vascular permeability; VEGF is 50,000 times more potent in inducing vascular leakage than histamine. The mechanism of this effect appears to be fenestration of the endothelium of small venules and capillaries through a Src kinase-dependent mechanism.
What are the 6 steps of angiogenesis ?
- ) Angiogenic signals are present
- ) Endothelial cells degrade the vascular membrane by releaseing MMPs
- ) Endothelial cells migrate, forming tip cells, toward the stimulus.
- ) Non-tip endothelial cells, stalk cells, proliferate and form a lumen
- ) Lumen extends toward the angiogenic signal through endothelial cell division and tip cell migration
- ) Two sprouts fuse their lumens to provide a route for blood flow
What immune cell is involved in angiogenesis ?
Mast cells are typically found at sites of neovascularization and are important mediators of the process because they release histamine. Histamine increases vascular permeability, causes vasodilation and stimulates angiogenesis.
What is arterogenesis ?
rapid proliferation of pre-existing collateral arteries. One of the main functions of arteriogenesis is to alleviate an occlusion in a major artery. Normally, less major arterioles are recruited, which must undergo significant vascular remodeling to thicken vascular walls and increase luminal diameter. This process is thought to be mediated by the pressure of the blood flow.
How do you inhibit angiogenesis ?
There are two agents currently used to inhibit pathologic angiogenesis: Anti-VEGF antibodies and tyrosine kinase inhibitors (TKI). There is more about this in the study questions.
How can angiogenesis be used as a cancer target ?
Angiogenesis is now being used as and anti-cancer target. Anti-angiogenic agents are used to starve the tumor and avoid intravasation of metastatic cells. Anti-lymphangiogenic agents are used to maintain chemotherapeutic levels and prevent metastases.
How can you control angiogenesis with transcriptional controls ?
HIF is molecule that regulates transcription and VEGF and EPO. HIF is only activated in hypoxic environments and can efficiently control the synthesis of the pro-angiogenic molecules so that they are only generated when they are needed. The other transcriptional regulators act in a similar fashion.
* EPO = erythropoietin: glycoprotein hormone that controls RBC production
How does hypoxes induce angiogenesis ?
Hypoxia inducible factor is stabilized by hypoxic conditions and upregulates several genes to promote survival in low-oxygen conditions. Gene products that result are glycolytic enzymes, VEGF and EPO. When oxygen becomes available again, HIF becomes inactive.
How can VEGEF therapy be refractory ?
Using and anti-VEGF therapy can result in remnants of the newly formed vasculature (“scaffolds of empty sleeves”) and pericytes. If the tumor develops different metabolic pathways and starts producing other pro-angiogenic molecules, the remnants can be re-activated and start growing again.
What are the guidance signals in angiogenesis ?
Tip cells extend the length of the growing capillary and are directed toward guidance signals (pro-angiogenic factors).
What do heparin and heparin sulfate do in angiogenesis ?
- ) Facilitates the binding of growth factors and growth factor receptors
- ) Increases the half-life of the growth factor.
What are angiopoietens ?
The angiopoietins are protein growth factors that promote angiogenesis.
What is the evidance for angiogenesis as a tumor target ?
1.) VEGF, mRNA and protein of VEGF are all up-regulated in tumor cells. An experiment mentioned in one of the readings demonstrated that when you alter the VEGF levels, tumor growth rates also changed.
What is bevacizumab ?
Bevacizumab is an angiogenesis inhibitor. Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A).
Why is HIF inhibition difficult to determine ?
Because all tissues, not just cancerous tissues, utilize HIF when they become hypoxic. If you use therapies that block this mechanism it might be detrimental to other organs.
