2. Introduction
• Vasculogenesis
de novo blood vessel generation from vascular progenitor cells
• Angiogenesis
Process of new blood vessel development from existing vessels.
• Arteriogenesis
Maturation of blood vessels via increasing the lumen of vessels
5. Angiogenesis
• Is important &
continuous process which
occur both in health &
disease.
• It is important as it is,
required for growth &
vitality of tissue.
10. 1.Formation of Tip cell with Pericyte
Detachment & BM degradation.
2. Proliferation of endothelial cells
just behind Tip cell.
3. Remodelling of capillary tubes.
4. Recruitment of periendothelial cells
to form mature vessel.
11. • In the process of angiogenesis,
• Tip cells migrate &
• Stalk cells proliferate & remain attached to
patent vessel.
12. Notch signalling
• This pathway through cross-talk with VEGF regulates
sprouting & branching of new vessel.
13. Factors determining angiogenesis
Inducers
• A) Growth factors : VEGF,
FGF , PDGF, TGF, Ang 1 .
• B) Cytokines : IL 1,6, 8.
• C) Proteases MMP,
Cathepsin
d) Others : Hypoxia & nitric
oxide synthase.
Inhibitors
• A) Growth inhibitors :
Endostatin, Platelet factor 4,
• IFN alpha.
• B). Cytokines ; IL 10,12
• C)Protease inhibitors :
TIMPs.
15. VASCULAR ENDOTHELIAL GROWTH
FACTOR
• Glycoproteins consisting of A-, B-, C-, D-, E- forms and
Placental Growth Factor (PlGF)
• Angiogenesis is primarily mediated through interaction
of VEGF-A with VEGFR-2
• VEGF RECEPTORS
• 3 types of receptors- VEGFR-1, VEGFR-2 (KDR, Flk-1),
VEGFR-3
• Tyrosine kinases
16.
17. • VEGF production is under control of :
hypoxia-inducible transcription factors(HIFs)
• VEGF receptor expression is up-regulated under:
• hypoxic or ischemic conditions.
18. • VEGF is a major factor in angiogenesis initiation because
of following
1. Endothelial cell survival
• 2. Stimulates endothelial division, induce
locomotion/migration
• 3. Induce the expression of proteases & receptors
• 4. Prevent endothelial cell apoptosis
• 5. Increase in vascular permeability by upregulating
second messengers such as NO
19.
20. Platelet-derived growth factor
• The platelet-derived growth factor (PDGF) regulates
• the recruitment of PERICYTES and
• smooth muscle cells
• required for further stabilization of the new
capillaries
21. Fibroblast growth factor
• Fibroblast growth factor (bFGF) family are also
potent inducers of angiogenesis.
• The effects of FGFs are mediated via high-affinity
tyrosine kinase receptors.
• Cellular responses mediated by FGFs include
• 1. cell migration
• 2. proliferation
• 3. differentiation
22. Cell adhesion molecules(CAM)
• 1. Integrins, cadherins
• 2.Vascular cell adhesion molecule-1,
• 3.P-selectin and E-selectin
• Integrins are expressed at high levels in :
• tumor vasculature and wound-healing tissues ,
• but at extremely low levels in normal blood vessels.
23. Integrins
• In contrast to normal endothelium, angiogenic
endothelium overexpresses specific members of
Integrin family.
• These mediate adhesion, migration & survival of
endothelial cells.
26. Plasminogen activator(PA) / plasmin system
• PAs activate plasminogen into plasmin, which degrade
several components of extracellular matrix (ECM)
• Both PAs and MMPs are secreted together with their
inhibitors.
• It ensures a stringent control of local proteolytic activity
31. Inhibitors of Angiogenesis
• ENDOSTATIN
• Produced by proteolytic cleavage of collagen
• ANGIOSTATIN
• Produced by proteolytic cleavage of plasminogen
• THROMBOSPONDIN-1(TSP-1)
• Adhesive glycoprotein in matrix.
• P53 up regulates TSP-1
35. Angiogenic switch
The molecular basis of angiogenic switch involves increased
production of angiogenic factors &/or loss of angiogenic
inhibitors.
• The normal healthy body maintains a perfect balance of
angiogenesis modulators.
36. • Angiogenesis occurs in healthy body for healing of wounds
&
• for restoring blood flow to tissues after injury or insult.
37. • Activation of coagulation pathway
• Formation of blood clot
• Release of cytokines, growth factors, chemokines
•
• Neutrophils (24 hrs)
• Proteolytic enzymes that clear debris
• Proliferation & migration of basal epithelial cells(24-48hrs)
• Macrophages (day 3)
• Formation of granulation tissue.
47. Retinopathy of prematurity
• ROP occurs because retina of preterm infant at birth is
incompletely vascularized & if postnatal environment
does not match in utero environment, the vessels &
neural retina will not grow normally.
• Angiogenesis is stimulated by “physiological hypoxia” of
developing retina, with secretion of VEGF by avascular
area .
48.
49.
50. Age related macular degeneration
• Most common cause of severe, irreversible vision
loss in older adults
• results from ageing & thinning of macular tissues
• Non-exudative (dry)
• Exudative (wet)
58. • The growth of primary & metastatic tumors to
> few mm requires
• recruitment of blood vessels and
• Vascular endothelial cells to support their
metabolic requirements.
59. • DUAL EFFECT on tumor growth
• Supplies nutrients & O2
• Newly formed ECs stimulate growth of adjacent
tumour cells by secreting growth factors –IGF,
PDGF
