Endothelial cells and angiogenesis Flashcards
What is angiogenesis?
Process by which new blood vessels are formed
Required many growth factors interacting together to promote the growth of blood vessels
When does angiogenesis happen in aults?
Reproduction
Wound healing
Due to low cell turnover
What is neovascularization?
Disease-associated angiogenesis and adults
What is an important growth factor in angiogenesis?
VEGF
Vascular Endothelial Growth Factor
Characteristics of VEGF
Secreted polypeptide
Binds to CS receptors on endothelial cells to regulate cell behaviour
Three roles of VEGF
Mitogen
Chemoattractant
Survival factor
What does the loss of one copy of the VEGF gene lead to?
Aberrant blood vessel formation and death in embryogenesis
What does VEGF do in pathology?
Regulates angiogenesis in many tumours and neovascular diseases
Describe the different mechanisms of blood vessel formation
Sprouting angiogenesis
Vasculogenesis
Intussusception
Vessel co-option
What is sprouting angiogenesis?
Endothelial cell becomes tip cell
Due to surrounding microenvironment
What is vasculogenesis?
Fromation of new blood vessels from endothelial progenitor cells in bone marrow
What is intussusception?
Formation of blood vessel within a blood vessel
Branches to form new vessels
What is vessel co-option?
Often seen in tumours
Group of cells come together and surround the blood vessel
Forms own blood supply
What are the 4 roles of adult angiogenesis?
Physiological roles - embryonic development, wound repair
Pathophysiological role - cancer
Cardiovascular disease - not enough angiogenesis = MI
Diabeted
Angiogenesis plays a very important role in cancer
TRUE or FALSE
TRUE
Angiogenic switch is an important factor in the development of a tumour
Describe the process of tumourgenesis
Somatic mutation - deletion or change in gene which gives it growth advantage to other cells
Formation of avascular tumour
As tumour grows it secretes angiogenic factors that stimulate angiogenesis of adjacent vessels
Formation of blood vessels into the tumour
How do blood vessels provide beneficial effects to the tumour?
Helps the tumour grow by providing it oxygen and nutrients
Provides highway for the tumour cells to extravasculate
How does a tumour stimulate angiogenesis?
Secretes angiogenic factors that stimulatre angiogenesis of adjacent vessels
What is the angiogenic switch?
Switch in balance from anti- to pro-angiogenic factors
What is the balance of angiogenic like in normal conditions?
Production of anti-angiogenic factors help offset the production of pro-angiogenic factors
Why does tumourgenesis cause angiogenic switch?
High production of pro-angiogenic factors in surrounding blood vessels
Due to secretion by tumour cells
Leads to imbalance
And switch to pro-angigenic phenotype
What are pro-angiogenic factors?
VEGF, FGF, PDGF
What are anti-angiogenic factors?
Angiostatin, Endostanin, Thrombospondin
What does the vascular network of a normal tissue look like?
Distinct vessel length
Distinct branch points
What does the vascular network of a tumour look like?
Chaotic architecture
Leaky
Areas of hypoxia
Thicker vessels
What does the tumour vasculature mean for the delivery of therapies?
Abnormalities reduce the delivery of therapies to the tissues
What is HIF-1?
Hypoxia inducible factor 1
Master regulator of the hypoxic response
Where is HIF 1 found?
In cells
What does HIF 1 do?
Regulator of tumour survival, progression and metastasis
HIF 1 is associated with increased patient mortality
What dos HIF 1 cause expression of?
VEGF
What happens to HIF 1 in oxygenated cells?
HIF - PH enxyme flags the degradation of HIF via proteasome pathways
What happens to HIF 1 in low levels of oxygen?
No HIF breakdown
HIF enters the nucleus where it dimerises and binds to HIF-responsive elements on genes
These genes are required for angiogensesis
Transcription of these genes to form mRNA
Leads to production of VEGF and PDGF
What important role does PDGF play?
Important role in tumour progression
Formation of vessel via angiogenic sprouting
VEGF selects the tip cell and binds to it
Gradient factors, VEGF and repression molecules cause stalk elongation and tip guidance
Sprout fusion, maturation and perfusion - two tips and stalks fuse
What does VEGF bind to?
VEGF receptors
Examples of VEGF receptors
VEGF-associated receptor 2
NRP1
What type of receptors are VEGF receptors?
Tyrosine kinases
What happens when VEGF binds to its receptor?
Association of signalling molecules
Progression of downstream signals
Cascades trigger motility, survival and gene expression
Coordinate the angiogenic response
VEGF are a family of secreted proteins - VEGF - A, -B, -C, -D, -E
TRUE or FALSE
TRUE
