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