Term
| Where do progenitor cells for Vasculogenesis in the adult arise from? |
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Definition
| Adult endothelia cells from bone marrow |
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Term
| What distinguishes Angiogenesis from Vasculogenesis? |
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Definition
1) Vasculogenesis is de novo
2) Angiogenesis is from existing vasculature due to local endothelial (normally-quiescent) proliferation, recruitment of ancillary cells (pericytes). |
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Term
| What do Kaposi's sarcoma, proliferative retinopathy, age-related macular degeneration and rheumatoid arthritis have in common? |
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Definition
| Pathological blood vessel formation. |
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Term
| What 6 factors initiate and influence vessel formation in order of event? |
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Definition
1) Hypoxia
2) Growth Factors
3) Proteases
4) ECM and degradation products
5) Shear Stress
6) Stretch (muscle) |
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Term
| What is the basic mechanism of hypoxia-induced vessel formation? |
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Definition
- Lack of oxygen in Parenchymal cells prevents turnover of HIF-1a, which up regulates transcription of genes such as VEGF, which cause vessel formation.
Remember, all mammalian cells are position 50-100 um from a capillary or less (i.e they can sense it!). |
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Term
| What important Growth factors/receptors are involves in vessel formation? |
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Definition
1) VEGF
- VEGF receptor 1- motility (really activates receptor 2)
-VEGF receptor 2-proliferation (primary receptor)
-Neuropilin 1(non-signaling)- co-receptor for VEGF that potentiates signal
- Heparan sulfate proteoglycans (non-signaling)- matrix sequestration
2) Angiopoietins (Ang 1, 2)
- binds Tie-1, Tie-2 receptors
- Ang 1 binds Tie-2 to attract ancillary cells and promotor maturation/growth
- Ang 2 is a Tie-2 antagonist
- Ang 1 is orphan |
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Term
| What are the important features of VEGFs? |
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Definition
1) 6 isoforms (5-heparin binding, 1 non-binding)
2) Spatially-restricted cue to branching and morphogenesis
3) Knock out heparin-binding- large lumens and few branches
4) Knock out non-heparin binding- more branching |
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Term
| What physiological effect would knocking out Angiopoiten 2 how on Vessel sprouting? |
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Definition
Ang-2 Inactivates Tie-2 and increases VEGF signaling, allowing for increased vessel sprouting.
Knocking it out would result in vessel regression. |
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Term
| Why does vascular growth proceed more rapidly from capillaries and post-capillary venules then from arteries? |
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Definition
| - These endothelial are surround by FAR FEWER CELLS. |
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Term
| How does proteolytic events enable vascular growth in capillaries and post-capillary venues? |
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Definition
| 1) Hypoxia induces VEGF expression and Ang-2 expression causes endothelial cells to produce proteases that break down matrix, which releases growth factors. |
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Term
| How does Ang-2/VEGF regulate Vessel sprouting/growth? |
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Definition
1) When Ang-2 is active along with VEGF, there is sprouting
2) When Ang-2 is active without VEGF, there is pruning. |
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Term
| How does Vasculogenesis occur in the Embryo? |
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Definition
Before vascularization, only obtains nutrition by diffusion
- Derived from mesoderm, begining from the yolk sack initially, and then arising from differentiation of ESCs.
- ESCs differentiatie into hemangioblasts through VEGF/VEGFR
- hemangioblasts differentiate into angioblast (become endothelial chords in endocardial tubes) and hematopoetic cells (become blood). |
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Term
| How does Angiogenesis occur in the Embryo and the Adult? |
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Definition
Need Ang, Tie, VEGF and VEGFRs!
1) Maturation of vessels via Ang/Tie signaling (knockouts cannot proceed with angiogensis)
2) Angiogensis begins to take over using resident endothelium instead of angioblast precursors that arise from ESCs.
2) VEGF and both VEGFR1 and VEGFR2 are critical. |
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Term
| How can VEGF isotype influence vasculature structure? |
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Definition
1) VEGF 120 non-heparin binding promotes large diameter leaky vessels
2) VEGF 164 and 188 heparin binding promotes small diameter, highly branching capillaries. |
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Term
| Describe the benefits and risks associated with 2 clinical approaches to enhancing angiogenesis. |
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Definition
Important for wound repair (diabetes and hypertension)
1) Bone Marrow injections to increase EPC count (circulating endothelial precursors)
2) Increase VEGF locally or systemically (gene therapy or injection)
** Too much VEGF can cause increased vascular permeability and edema, which is contraindicated for wound healing). |
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Term
| Describe the benefits and risks associated with 2 clinical approaches to inhibiting angiogenesis. |
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Definition
Used for tumor-growth inhibition!
1) Remove VEGF entirely
- with a neutralizing antibody/fragment (Bevacizumab/Avistin) to the soluble VEGF receptor
- With RNA Aptamers that inhibit VEGF/receptor interactions.
2) Inhibit VEGF receptor signaling
- tyrosine kinase inhibitors
- Block binding with an antibody (IMC-IC11)
3) ECM breakdown products that interact with endothelium.
4) Natural MMP (matrix metalloprotease) inhibitor Neovastat. |
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Term
What are the actions of each of the following approved anti-angiogensis drugs currently approved for use in the U.S.?
1) Avastin
2) Tarceva
3) Nexavar
4) Revlimid
5) Sutent |
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Definition
1) Colorectal cancer (neutralizing VEGF antibody)
2) Lung Cancer (EGF tyrosine kinase inhibitor)
3) Renal Cell Carcinoma (multiple tyrosine kinase inhibitor for both blood and vessel growth)
4) Myelodysplastic syndrome (thalidomide analogue) reduced VEGF
5) Advanced kidney cancer and GI stromal tumors (multiple tyrosine kinase inhibitor). |
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