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TRANSCRIPT
L. Benjamin & E. Keshet
New blood vessel formation(revascularisation/angiogenesis)
• blood vessel structure (varies between tissues) • Cellular mechanisms (capillary sprouting)
• Angiogenic factors (VEGF, FGF)
• Anti-angiogenic drugs• Applications (disease, tumours, regeneration)
New blood vessel formation(revascularisation/angiogenesis)
Blood vessel structure• Focus on capillaries:
–structure varies between tissues• Endothelial cells• Pericytes• Smooth muscle cells
Cleaver 6 Melton, 2003
Phenotypes of differentiated endothelial cells
Blood brain barrier CNS Lymph nodes High endothelial
venules
fenestraeKidney glomeruli Gastrointestinal tract
fenestrae
liver Large gaps
spleen Splenic sinus of red pulp
Ross & Rommel(1995) HISTOLOGY
Ross & Rommel(1995) HISTOLOGY
BLOOD
BLOOD
Leukocytes crossing between junctionsDejana E (2006) The transcellular railway: insights into leukocyte diapedesis
Nature 8:105-107
Leukocytes penetrating the endotheliumDejana E (2006) The transcellular railway: insights into leukocyte diapedesis
Nature 8:105-107
New blood vessel formation(revascularisation/angiogenesis)
• Blood vessel structure (varies between tissues)
• Cellular mechanisms (capillary sprouting)
• Angiogenic factors (VEGF, FGF)
• Anti-angiogenic drugs• Applications (disease, tumours, exercise, regeneration)
New blood vessel formation(revascularisation/angiogenesis)
Angiogenic factors • VEGF = ONLY mitogenic for endothelial cells• FGF = mitogenic for many cell types
• Angiopoietin GFs, MMPs, Exercise
Capillary sprouting = angiogenesis
Folkman J (2007)
Folkman J (2007)
BMDC recruitment in tumors
Angiogenic factors, cytokines initiate recruitment
BMDC mobilization
Transendothelial migration
Homing of BMDCs to tumor
Amplification of hematopoietic lineages
Folkman J (2007)
New blood vessel formation(revascularisation/angiogenesis)
• Anti-angiogenic drugs
3 general mechanisms of angiogenesis inhibitors
Folkman J (2007)
Anti-angiogenic factors and Geneticse.g. Downs syndrome – increased circulating endostatinresults in decreased tumour incidence
Applications of drugs to influence angiogenesis
• DiseaseMacular degeneration/ eye (due to increased blood vessels = block)Cancer and tumour growth (requires angiogenesis = block)
• Tissue regeneration (requires angiogenesis = increase)
Angiogenesis = growth of blood vessel sprouts from capillary blood vessels
Depends on angiogenic factors and their inhibitors
Angiogenesis is required for • growth of many normal tissues– bone, prostate• repair of many damaged tissues• increase in adipose tissue• tumour growth
Folkman J (2007) Nature Reviews/ Drug discovery. April 6:273-286