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PMY2106 > Angiogenesis 1 > Flashcards

Angiogenesis 1 Flashcards

1
Q

endothelial cells

A
  • line blood vessels
  • surface area 6000m2
  • divide rarely in adult life
  • capable of rapid division in response to the right stimuli
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2
Q

two processed responsible for formation of new blood vessels

A
  • vasculogenesis
  • angiogenesis
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3
Q

mural cells

A
  • 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
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4
Q

Vasculogenesis

A
  • “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
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5
Q

angioblasts in vasculogenesis

A

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

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6
Q

angiogenesis

A
  • “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
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7
Q

when angiogenesis occurs

A
  • 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
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8
Q

balancing angiogenic signals

A
  • 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
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9
Q

if angiogenesis stimulator > angiogenesis inhibitor pathologically

A
  • angiogenic switch is “on”
  • cancer, ocular disorders, rheumatoid arthritis
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10
Q

if angiogenesis inhibitor > angiogenesis stimulator pathologically

A

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

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11
Q

when pathological angiogenesis occurs

A
  • diabetic retinopathy: loss of vision
  • cancer
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12
Q
  • diabetic retinopathy: loss of vision
  • cancer
A
  • 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
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13
Q

diabetic retinopathy

A
  • vaso degeneration in microvascular beds
  • accompanied by neo-vascularisation
  • leaky blood vessel formation in macular of the retina
  • can lead to blindness
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14
Q

cancer

A
  • 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
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15
Q

cancer-triggered angiogenesis

A
  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
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16
Q

endogenous angiogenesis inducers

A
  • VEGF
  • angiopoietin
  • FGF-2
  • PDGF
  • all regulated by intracellular/soluble tyrosine kinase inhibitors
17
Q

regulation of angiogenesis

A
  • 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
18
Q

vascular endothelial growth factor (VEGF)

A
  • 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
19
Q

growth factors and cytokines that induce VEGF mRNA transcription

A
  • PDGF
  • epidermal growth factor (EGF)
  • TNF-alpha
  • TGF-beta
  • interleukin 1b (IL-1b)
20
Q

VEGF regulation

A
  • 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
21
Q

VEGF receptors

A

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

22
Q

platelet derived growth factor

A
  • 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
23
Q

PDGF-BB

A
  • 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
24
Q

basement membrane breakdown by proteolysis

A
  • 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
25
Q

stromal cells

A
  • cells that contribute to the development of multiple tissues and blood cells
  • compromises of fibroblastic, inflammatory and immune cells
  • additional source of angiogenic factors
26
Q

tumour cells

A
  • 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
27
Q

capillary formation and vessel maturation

A
  • 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

PMY2106 (15 decks)

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