Lecture 19 : Angiogenesis Role of VEGF and Hypoxia Flashcards
What is Vasculogenesis?
Vasculogenesis is the embryonic formation of endothelial cells from the mesoderm layer precursors to form new blood vessels in blood islands.
What does Vasculogenesis give rise to?
Vasculogenesis give rise to the heart and the first primitive vascular plexus inside the embryo and in its surrounding membranes.
Vasculogenesis is …?
Embryonic
What happens during Vasculogenesis?
During Vasculogenesis,
- Blood vessel formation first occurs in the wall of the yolk sac (Figure A)
- Undifferentiated mesenchyme cells condense to form Angiogenetic cell clusters (Figure B)
- These centers of Angiogenetic cell clusters (Figure B) form the blood cells form the primitive blood cells (Figure C)
- The outsides of the Angiogenetic Cell Clusters develop into blood vessel Endothelial Cells
Where do Vascular development in the embryo and extra-embryonic membranes occur?
The Vascular System form in two specific sites in the embryo:
- One in the blood islands of the yolk sac
- The other in the embryo proper
What is Angiogenesis
Angiogenesis is the process by which new blood vessels from pre-existing vessels that are formed in the early stages of vasculogenesis.
What are the two stages of Angiogenesis?
- Sprouting Angiogenesis
- Intussusceptive Angiogenesis
What is Sprouting Angiogenesis?
Sprouting Angiogenesis is when tissues that have low nutrient and oxygen supply will produce signals (VEGF-A) that induces endothelial cells to secrete proteases that degrade their basement membranes and allow the endothelial cells to escape their original vessel walls.
These cells continue to proliferate and form sprouts connecting neighboring vessels, guided by extending towards the source of the angiogenic signal.
- Basically… Low Oxygen and Nutrients produces VEGF-A signals
- VEGF-A signals induce endothelial cells to secrete proteases to disintegrate (degrade) their basement membranes and run away.
- This is done so the endothelial cells can escape from their original vessel walls.
- These same runaway endothelial cells will keep making copes if themselves and make sprouts that connect to neighboring vessels.
- They’re running towards the source of the angiogenic signal.
- The sprouts that these runaway endothelial cells are making that connect them to their neighbor vessels are all done while they’re following the origin of that angiogenic signal
- They’re running towards the source of the angiogenic signal.
What is Intussusceptive Angiogenesis?
Intussusceptive Angiogenesis is also known as splitting angiogenesis, which is the formation of new vessels by splitting a pre-existing vessel in two.
Basically…
- Making a new blood vessel by splitting an existing blood vessel into two.
- Turning one existing blood vessel into two blood vessels ~~~~~
What is Happening in the Diagram?
Angiogenesis is happening,
Angiogenesis is the formation of new blood vessels from existing blood vessels,
Can be either:
- Sprouting Angiogenesis
- or
- Inusscepetive Angiogenesis
What are examples of Angiogenesis in Adults?
Angiogenesis in the uterine lining,
- In Women, Angiogenesis happens each month for a few days in the lining of their uterus.
- This happens during their Menstrual Cycle
- New blood vessels are formed from their existing ones (Angiogenesis)
Angiogenesis in tissue during wound healing,
- Angiogenesis happens in our tissue when we get hurt,
- New blood vessels are made from existing ones (Angiogenesis) to heal our tissue when we get hurt.
Explain this Slide
Not sure if this slide is super important
- The largest blood vessels are Arteries and Veins
- Arteries have Veins have a thick layer of connective tissue and many smooth muscle cells
- Arteries and Veins will have varying thicknesses depending on the diameter and function of those vessels.
-
Blood vessel interiors are only made from a single layer of endothelial cells.
- This single layer of endothelial cells is attached to and separated from the other layers of the basal lamina.
- The finest branches of the vascular system are the capillaries and sinusoids.
- These are composed of endothelial cells and a basal lamina put together with a few perictytes.
- Members of the connective-tissue family
- related to vascular smooth muscle cells
- Pericytes wrap themselves around the small vessels that have other important functions
What are the different Characteristics of Arteries, Veins, and Capillaries?
….Capillaries are the smallest of these blood vessels
Describe Capilaries
Capillaries are:
- very thing
- composed of a single layer of endothelial cells
- can be:
- continuous
- Fenestrated
- Sinusoid
- Have incomplete basement membrane
What’s the hardest part of the binding process of Oxygen to Tissue?
Binding the first oxygen is the hardest step, one the first one binds, the others will bind more easily.
Check this again, slide 15
What is pO2?
pO2 is a measure of how much O2 is dissolved in the blood.
What is right shift?
If you become acidotic
How many molecules of Oxygen can Hemoglobin found in RBCs bind to?
4 molecules of Oxygen
Go over what he said for slide 16
….
What are the signalling mechanisms driving Vasculogenesis and Angiogenesis?
Fibroblast Growth Factor 2
VEGf, by one of it’s two receptors
As you form the initial tube,…., you’ll have a new system involving Ang1 signalling through Tie1 and 2?
Slide 17
Neutralizing antibodies against VEGF block results in?
Embryonic development
Bone morphogenesis
Female reproductive cycling
Corneal angiogenesis
Growth of several tumor types in animal models
What is the most critical factor for embryonic angiogenesis?
VEGF
Blocking VEGF =?
Lethal
even 50% reduction of VEGF is lethal
What is the main VEGF?
VEGF A
???? Explaining Slide 20
What’s happening?
?? What happens during Sprouting Angiogenesis?
When endothelial cell gets the right signal (VEGF A), its gets pseudopdial process and go into surrounding tissue
learns to new sprout, new cappilary forming
signal for this is high or low oxygen in surrounding tissue
High Oxygen = Hypoxia Induced Factor
degraded
Low Oxygen = HIF levels build up
stimulates transcription and build up of VEGF A, signal for Angiogenesis to take place
?????What is HIF-1 regulated?
???? Hypoxia pathway slide 24
oxygenaes it, ….., degrade
under hypox conditions, no … take places, … Hif 1B, targets various genes for ….
??? Slide 25
?????
??????? Slide 26 How is VEGF-A regulated?
……..
Under normal conditions,,
?????? Slide 27
HIF1a is regulated at….
complex process involving .. HIF1A domain
end and C domain??
transactivating domains turn on different sets of genes
binding of HIF1a factor leads to… factor?
adequate supply, …. also HIF argenile hyd…
p300 doesn’t bind to gene?
????? Slide 28?
Depending upon level of oxygen…
regulation of this gene will be tightly controlled
What does Ang-1 do?
Ang-1 promotes vessel maturation by stimulating migration, adhesion, and survival of endothelial cells
What does Ang-2 do?
Ang-2 disrupts connections between the endothelium and perivascular cells
What does Ang-2 do in combination with VEGF?
In combination with VEGF, Ang-2 promotes neo-vascularization
Ang-2 is an antagonist of ____ and does ____
Importantly, Ang-2 is an antagonist of Ang-1 and blocks its ability to bind to the Tie-2 receptor.
How can Ang-2 have different effects?
Ang-2 has different effects depending upon whether VEGF is present or not
What receptors function in Angiogenesis?
Angiopoietins 1/2 and TIE receptors
???? What is going on in Slide 30?
…….
Need to have both VEGF and ANG 2 to???
??? Slide 30
Explain how Angiopoietin/Tie-2 Receptor Signalling takes place
… lead to cell survival
produced by periocyte?
can also signal through by signaling ???
Just to give reference??
Not important to know all the details here,
main point is Ang1 qupoisent state
and 2 antigonizes, …. in presence of VEGf
???? Slide 33
..Angiopoetin 1 is maintaining..
in regions where you need new capillaries, Angio1 drops off and 2 comes up,
result is formation of sprouts and branching structures and everything
will grow into region that’s hypxic, knows its hypoxic bc of high conc of VEGF… something..
Targeted growth of blood vessels in regions where it’s needed
if you get it where it’s not needed, you have other problems
????????What is PDGF?
necesaary for the proliferation of pericytes and smooth muscle cells.
released and associated wit ECM,…
signals to periocytes to migrate and proliferate,,..
have …
can maintain them in their mature form
