Angiogenesis 1

Question 1

endothelial cells

Answer 1

• line blood vessels
• surface area 6000m2
• divide rarely in adult life
• capable of rapid division in response to the right stimuli

Question 2

two processed responsible for formation of new blood vessels

Answer 2

• vasculogenesis
• angiogenesis

Question 3

mural cells

Answer 3

• vascular smooth muscle cells and pericytes of the microcirculation
• both types are in close contact with the endothelial cells lining capillaries
• important for vascular development and stability

Question 4

Vasculogenesis

Answer 4

• “the differentiation of precursor cells into endothelial cells and the de novo formation of a primitive vascular network”
• occurs during embryogenesis
• blood islands composed of progenitor cells of blood cells (hematopoietic cells) and endothelial cells (angioblasts) differentiate from the mesoderm

Question 5

angioblasts in vasculogenesis

Answer 5

they form the primordial vascular network, consisting of the major blood vessels of the embryo

Question 6

angiogenesis

Answer 6

• “formation of vascular sprouts from pre-existing vessels”
• results in highly branches vascular plexus
• this primary capillary plexus is remodeled several times until a mature vascular system consisting of vessels of different diameters and functions is formed
• occurs during development and in postnatal life

Question 7

when angiogenesis occurs

Answer 7

• blood vessel formation in placenta
• wound healing
• for these purposes, angiogenesis is highly regulated, turned on for a short period of time and then completely inhibited

Question 8

balancing angiogenic signals

Answer 8

• angiogenesis is controlled with “on” and “off” switches in a healthy individual
• “on” switches are known as angiogenesis-stimulating growth factors
• “off” switches are known as angiogenesis inhibitors
• angiogenesis is “turned off” by production of more inhibitors than stimulators

Question 9

if angiogenesis stimulator > angiogenesis inhibitor pathologically

Answer 9

• angiogenic switch is “on”
• cancer, ocular disorders, rheumatoid arthritis

Question 10

if angiogenesis inhibitor > angiogenesis stimulator pathologically

Answer 10

heart disease and other pathologies associated with impaired neo-vascularisation capacity

Question 11

when pathological angiogenesis occurs

Answer 11

• diabetic retinopathy: loss of vision
• cancer

Question 12

• diabetic retinopathy: loss of vision
• cancer

Answer 12

• age related macular degeneration, major cause of blindness
• can be dry or wet
• diagnosing factor is presence of neovascularisation
• new blood vessels invade the retina and leaky blood vessels occlude the retina

Question 13

diabetic retinopathy

Answer 13

• vaso degeneration in microvascular beds
• accompanied by neo-vascularisation
• leaky blood vessel formation in macular of the retina
• can lead to blindness

Question 14

cancer

Answer 14

• angiogenesis-dependent process
• a growing tumour needs an extensive vascular network to provide nutrients and oxygen
• new intratumoural blood vessels provide a way for tumour cells to enter circulation and to metastatise to distant organs

Question 15

cancer-triggered angiogenesis

Answer 15

1. small oxygen-deprived tumour sends signals to blood vessels
2. angiogenic factors released
3. sprouting capillary brings nutrients to tumour
4. tumour growth and metastatic spread

Question 16

endogenous angiogenesis inducers

Answer 16

• VEGF
• angiopoietin
• FGF-2
• PDGF
• all regulated by intracellular/soluble tyrosine kinase inhibitors

Question 17

regulation of angiogenesis

Answer 17

• is complex and involves multiplex signaling cascades
• several receptor mediated events
• VEGF is a main player and drug target
• intracellular signaling cascades by tyrosine kinases are the main drug target

Question 18

vascular endothelial growth factor (VEGF)

Answer 18

• expressed in many tissues, including brain, kidney, liver and spleen
• in vivo, VEGF regulates vascular permeability which is important for initiation of angiogenesis
• loss of a single VEGF allele leads to embryonic lethality, so must play an irreplaceable role in development of vascular system
• transcription of VEGF mRNA induced by variety of growth factors and cytokines

Question 19

growth factors and cytokines that induce VEGF mRNA transcription

Answer 19

• PDGF
• epidermal growth factor (EGF)
• TNF-alpha
• TGF-beta
• interleukin 1b (IL-1b)

Question 20

VEGF regulation

Answer 20

• VEGF levels also regulated by tissue oxygen tension
• hypoxic upregulation of VEGF provides mechanism by which tissues or tumours can increase their oxygenation through induction of blood vessel growth
• normoxia downregulates VEGF production
• these competing processes ensure vasculature is tuned to metabolic needs of the tissue

Question 21

VEGF receptors

Answer 21

two high affinity tyrosine-kinase receptors for VEGF have been identified on vascular endothelium:
- VEGFR-1
- VEGFR-2
- regulation of VEGF receptor gene expression regulated by hypoxia

Question 22

platelet derived growth factor

Answer 22

• secreted by blood platelets and endothelial cells in an area of injury, this is an agent that stimulates fibroblasts to multiply and synthesize collagen
• exists as a homodimer

Question 23

PDGF-BB

Answer 23

• mediates angiogenesis at multiple points in the cascade by:
  1. binding to its receptor PDGF-BR on vascular endothelium
  2. inducing production of VEGF
  3. activating intracellular signal transduction pathways
  4. stimulating endothelial proliferation
  5. promoting endothelial migration
  6. facilitating vascular tube formation
  7. recruiting smooth muscle cells and pericytes to stabilize newly formed vasculature

Question 24

basement membrane breakdown by proteolysis

Answer 24

• degradation of underlying basement membrane and invasion of stroma of surrounding tissue are required to begin formation of new capillary sprouts
• these processes require cooperative activity of urokinase-plasminogen activator (uPA) and matrix metalloproteinase (MMP) enzyme systems

Question 25

stromal cells

Answer 25

- cells that contribute to the development of multiple tissues and blood cells - compromises of fibroblastic, inflammatory and immune cells - additional source of angiogenic factors

Question 26

tumour cells

Answer 26

- produce VEGF and other angiogenic factors - these stimulate resident endothelial cells to proliferate and migrate - tumour cells may also release stromal cell-recruitment factors such as PDGF-A, PDGF-C or TGF-beta

Question 27

capillary formation and vessel maturation

Answer 27

- newly forming capillaries synthesise a new basement membrane (extracellular proteolysis must be locally inhibited to permit assembly of ECM components) - once capillary sprout is formed, degradation of newly formed ECM occurs at tip of sprout, which allows further invasion - capillary formation results from alternative cycles of activation and inhibition of extracellular proteolysis - stabilisation of new capillaries require recruitment of pericytes and smooth muscle cells, which is regulated by PDGR - when sufficient neovascularization has occurred, angiogenic factors are downregulated and the endothelial cells become quiescent