VEGF Signaling – An overview

Presented by Prabhu T, Research scholar, Dept .of Biotechnology. Sahyadri science college, Shimoga

20th January,2013

1- Vasculogenesis - Angiogenesis - Arteriogenesis

VasculogenesisFormation of blood vessels by differentiation from (hem)angioblasts

Sprouting angiogenesisSprouting of cells from mature endothelial cells of the vessel wall

Arteriogenesisgrowth of large arteries from pre-existing small vessels/capillaries

LymphangiogenesisFormation of the lymphatic vasculature

Life time of endothelial cells:

months (lung, liver) to years (brain, muscle)

Slow repair and renewal of vascular wall

New vessel formation:

Embryo, growthIn uterus, during menstruation cycleWound repair

Sprouting towards chemotactic gradient: VEGF

Hypoxia - HIF - VEGFevery cell must be within 50 to 100 mm of a capillary

HIF: hypoxia inducible factorVEGF: vascular endothelial growth factor

VEGF/VEGFR:VEGF-A: initiation of vasculogenesisand sprouting angiogenesis,Immature vessels,Vascular permeability factor,Haploid insufficiency in k.o. mice,

PlGF: remodeling of adult vessels VEGF-B: heart vascularization VEGF-C: lymphatic vesselsVEGF-D: lymphatic vessels

VEGFR-2: growth and permeabilityVEGFR-1: negative role , decoy receptor,

synergism with VEGFR-2 in tumor angiogenesis VEGFR-3: lymphatic vessels

VEGF/VEGFR family

VEGF signaling pathways

Ras/MAP kinase pathway – Gene expression and proliferation

Akt/PI3K pathway – cell survival

NOS pathway – vascularpermeability

PKC pathway – cell proliferation and vascularpermeability

FAK/Paxillin pathway – cytoskeletal rearrangement and cell migration

Angiogenesis

Ras/MAP kinase pathway

VEGF VEGF

Grb-2 Adaptor: SH2- Domain

SOS is a Ras-GEF (guanine nucleotide exchange factor)

Ras: GTP-binding Protein (Oncogene detected in Rat Sarcoma)

SOS

Ras activates MAP-Kinase Pathway

1- MAPKKK2- MAPKK3- MAPK

MAPK: Mitogen-activated Kinase

(there are three MAP-Kinase cascades:MEK/ERKP38JNK)

Raf

MEK

ERK

f

The phosphorylated MAPK ERK is transported into the nucleusand phosphorylates the transcription factor TCF

ERK: extracellular signal regulated kinaseTCF: ternary complex factorSRF: serum response factorSRE: serum response element

(DNA binding sequence for TCF and SRF in promoter of different genes)

Genes forCell cycle/Proliferation,e.g. c-Fos,TCFSRF and Jun

PKC signaling pathway

PKB, PDK:(PDK: PI-dependent kinase)

Ser/Thr kinases

Akt/PI-3 Kinase Pathway and Survival

VEGF

Talin and Vinculin

Angiogenesis-dependent diseases

excessCancer

Infantile hemangiomas

Autoimmune diseases, chronic inflammatory diseases:Rheumatoid arthritisPsoriasis

Age-related macular degeneration

Atherosclerosis

Deficiency:Limb ischemiaMyocardial ischemia

References

Books:

B. Alberts et al., Molecular Biology of the Cell,5th Edition, Taylor and Francis Inc., 2007Pg. 1279-1283

Endothelial BiomedicineW. Aird, ed.Cambridge University Press, 2007

R.A. Weinberg, The Biology of Cancer, Garland Science, 2007Pg. 556-585

Tumor Angiogenesis - Basic mechanisms and Cancer Therapy, D. Marme, N. Fusenig, ed.Springer Verlag 2008

By,Prabhu T,20th January,2013