ANGIOGENESIS IN DERMATOLOGY
BY
KHALID M. GHARIB
Lecturer of Dermatology and
Venereology Zagazig University
• Angiogenesis is an important process in normal
physiology and disease pathogenesis.
• Angiogenesis is controlled in a he...
• Angiogenesis is the growth of new blood vessels
from preexisting ones.
• It is a normal process in growth, development,
...
• Angiogenesis is induced when there is an
imbalance of angiogenic growth factors
compared to angiogenesis inhibitors
KHAL...
KHALID M. GHARIB
5
KHALID M. GHARIB
6
ANGIOGENIC GROWTH FACTORS
• Vascular endothelial growth factor
(VEGF) is thought to be the most potent and
predominant ang...
Angiopoietin
• The binding of angiopoietin 1 (Ang1) to Tie2
activates the receptor through
autophosphorylation and promote...
Basic fibroblast growth factor
bFGF is produced by keratinocytes and acts as a
mitogen for both endothelial cells and
kera...
Interleukin-8
• Interleukin-8 is a proinflammatory and
proangiogenic factor that binds to G proteine
coupled receptors, ac...
Platelet-derived growth factor
PDGF has been shown to play an analogous role
to VEGF in nonmammalian vertebrates and is
cr...
Tumor necrosis factor alfa
• TNFa activates B cells and the MAPK pathway to
induce upregulation of other angiogenic factor...
Transforming growth factor beta
• TGFb normally acts as a tumor suppressor but
can promote tumor angiogenesis when
aberran...
ANGIOGENESIS INHIBITORS
Angiostatin
• Angiostatin inhibits endothelial cell
proliferation and stimulates endothelial cell
...
Endostatin
Endostatin inhibits endothelial cell proliferation
and angiogenesis by competitively binding to
VEGFR2
Endostat...
Thrombospondin-1
• Thrombospondin-1 inhibits endothelial cell
migration and inhibits the activity of VEGF,
bFGF, IL-8, and...
Interferons alfa and beta
• Interferons alfa and beta are thought to inhibit
angiogenesis by down-regulating IL- 8, bFGF,
...
Interleukin-12 and interferon gamma
• IL-12 suppresses angiogenesis through the
induction of interferon gamma
KHALID M. GH...
Tissue inhibitors of matrix
metalloproteinases
• Tissue inhibitors of matrix metalloproteinases
have the critical role of ...
Additional elements central to
angiogenesis
• PI3K/Akt/mTOR pathway
The PI3K/Akt signaling pathway is central to the
regul...
KHALID M. GHARIB
21
Ranibizumab,Pegaptanib, Bevacizumab
are an antibody fragment that binds to and
inhibits the activity of VEGF and is design...
KHALID M. GHARIB
23
KHALID M. GHARIB
24
Imiquimod
• Imiquimod is a topical cream that inhibits
angiogenesis by the induction of cytokines that
inhibit angiogenesi...
Other drugs
Thalidomide Interferon-alfa2b
Thalidomide exerts its
antiangiogenic effects by
down-regulating VEGF and
bFGF, ...
THERAPEUTIC AGENTS AVAILABLE FOR
ANGIOGENESIS PROMOTION
• Recombinant human platelet-derived
growth factor
• Becaplermin i...
ANGIOGENESIS IN CUTANEOUS DISEASE
Common diseases Other diseases
• Squamous cell carcinoma
• Kaposi sarcoma
• Pyogenic gra...
Pyogenic granulomas
• Pyogenic granulomas express many angiogenic
factors
• Topical imiquimod has been reported as a
succe...
Kaposi sarcoma
• The KS herpesvirus is believed to induce
angiogenesis via the PI3K/Akt pathway
• Sirolimus, imiquimod, an...
Psoriasis
• Angiogenesis is thought to play a role in the dilated
vasculature of the papillary dermis in psoriasis
• Sirol...
KHALID M. GHARIB
32
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Angiogenesis in dermatology

  1. 1. ANGIOGENESIS IN DERMATOLOGY BY KHALID M. GHARIB Lecturer of Dermatology and Venereology Zagazig University
  2. 2. • Angiogenesis is an important process in normal physiology and disease pathogenesis. • Angiogenesis is controlled in a healthy body by a system of angiogenic growth factors and angiogenesis inhibitors. When angiogenic growth factors are predominantly expressed, blood vessel growth occurs and disease may result. • Successful therapies have been developed that target growth factors, their receptors, or the cascade pathways that are activated by growth factor/receptor interactions. KHALID M. GHARIB 2
  3. 3. • Angiogenesis is the growth of new blood vessels from preexisting ones. • It is a normal process in growth, development, the female reproductive cycle, and wound healing. • However, it is also a key element in disease pathogenesis KHALID M. GHARIB 3
  4. 4. • Angiogenesis is induced when there is an imbalance of angiogenic growth factors compared to angiogenesis inhibitors KHALID M. GHARIB 4
  5. 5. KHALID M. GHARIB 5
  6. 6. KHALID M. GHARIB 6
  7. 7. ANGIOGENIC GROWTH FACTORS • Vascular endothelial growth factor (VEGF) is thought to be the most potent and predominant angiogenesis stimulator • VEGF binds to tyrosine kinase receptors • VEGF effects are mediated through multiple pathways KHALID M. GHARIB 7
  8. 8. Angiopoietin • The binding of angiopoietin 1 (Ang1) to Tie2 activates the receptor through autophosphorylation and promotes endothelial cell migration and survival. • Ang2 may function as an antagonist to Ang1 KHALID M. GHARIB 8
  9. 9. Basic fibroblast growth factor bFGF is produced by keratinocytes and acts as a mitogen for both endothelial cells and keratinocytes. bFGF has been linked to the pathogenesis of many cancers, including malignant melanoma KHALID M. GHARIB 9
  10. 10. Interleukin-8 • Interleukin-8 is a proinflammatory and proangiogenic factor that binds to G proteine coupled receptors, activating the downstream pathway of PI3K/Akt and MAPK to control cell survival, angiogenesis, and migration KHALID M. GHARIB 10
  11. 11. Platelet-derived growth factor PDGF has been shown to play an analogous role to VEGF in nonmammalian vertebrates and is crucial in early mammalian embryogenesis and organogenesis. • PDGF has also been shown to promote dermal wound healing and is strongly linked to fibrotic diseases, such as scleroderma. KHALID M. GHARIB 11
  12. 12. Tumor necrosis factor alfa • TNFa activates B cells and the MAPK pathway to induce upregulation of other angiogenic factors, including IL-8, VEGF, and MMPs KHALID M. GHARIB 12
  13. 13. Transforming growth factor beta • TGFb normally acts as a tumor suppressor but can promote tumor angiogenesis when aberrantly expressed KHALID M. GHARIB 13
  14. 14. ANGIOGENESIS INHIBITORS Angiostatin • Angiostatin inhibits endothelial cell proliferation and stimulates endothelial cell apoptosis, possibly through the inhibition of bFGF and VEGF KHALID M. GHARIB 14
  15. 15. Endostatin Endostatin inhibits endothelial cell proliferation and angiogenesis by competitively binding to VEGFR2 Endostatin also blocks the effects of bFGF • and various MMPs KHALID M. GHARIB 15
  16. 16. Thrombospondin-1 • Thrombospondin-1 inhibits endothelial cell migration and inhibits the activity of VEGF, bFGF, IL-8, and MMP-9 KHALID M. GHARIB 16
  17. 17. Interferons alfa and beta • Interferons alfa and beta are thought to inhibit angiogenesis by down-regulating IL- 8, bFGF, and MMP-9 KHALID M. GHARIB 17
  18. 18. Interleukin-12 and interferon gamma • IL-12 suppresses angiogenesis through the induction of interferon gamma KHALID M. GHARIB 18
  19. 19. Tissue inhibitors of matrix metalloproteinases • Tissue inhibitors of matrix metalloproteinases have the critical role of counterbalancing the activity of MMPs, to prevent the uncontrolled destruction of tissue KHALID M. GHARIB 19
  20. 20. Additional elements central to angiogenesis • PI3K/Akt/mTOR pathway The PI3K/Akt signaling pathway is central to the regulation of angiogenesis and other cellular processes • Many angiogenic growth factors phosphorylate PI3K resulting in the activation of Akt, which leads to inhibition of endothelial cell apoptosis. • mTOR :Mammalian target of rapamycin • (PI3K)/Akt :The phosphatidylinositol 3-kinase KHALID M. GHARIB 20
  21. 21. KHALID M. GHARIB 21
  22. 22. Ranibizumab,Pegaptanib, Bevacizumab are an antibody fragment that binds to and inhibits the activity of VEGF and is designed for intraocular use KHALID M. GHARIB 22
  23. 23. KHALID M. GHARIB 23
  24. 24. KHALID M. GHARIB 24
  25. 25. Imiquimod • Imiquimod is a topical cream that inhibits angiogenesis by the induction of cytokines that inhibit angiogenesis, up-regulation of endogenous angiogenesis inhibitors, and down-regulation of local proangiogenic Factors • Imiquimod has been used off-label to treat angiogenic-dependent dermatologic disease KHALID M. GHARIB 25
  26. 26. Other drugs Thalidomide Interferon-alfa2b Thalidomide exerts its antiangiogenic effects by down-regulating VEGF and bFGF, and may also inhibit TNF-a, IL-6, IL-12, IGF-1, and NF-kB IFNa2b is a synthetic cytokine that is thought to inhibit angiogenesis by down- regulating angiogenic factors Use of this drug has been limited because of the risk of spastic diplegia KHALID M. GHARIB 26
  27. 27. THERAPEUTIC AGENTS AVAILABLE FOR ANGIOGENESIS PROMOTION • Recombinant human platelet-derived growth factor • Becaplermin is a topically administered recombinant human PDGF used for promoting • wound repair KHALID M. GHARIB 27
  28. 28. ANGIOGENESIS IN CUTANEOUS DISEASE Common diseases Other diseases • Squamous cell carcinoma • Kaposi sarcoma • Pyogenic granulomas, • angiofibromas, • psoriasis, • rosacea, • atopic dermatitis, • keloids • fibrohistiocytic tumors, • Malignant melanoma, • cutaneous lymphoma, • angiosarcoma, • hemangiomas, hemangioendotheliomas, • vascular malformations,, and • diabetic ulcers KHALID M. GHARIB 28
  29. 29. Pyogenic granulomas • Pyogenic granulomas express many angiogenic factors • Topical imiquimod has been reported as a successful treatment for pyogenic granulomas KHALID M. GHARIB 29
  30. 30. Kaposi sarcoma • The KS herpesvirus is believed to induce angiogenesis via the PI3K/Akt pathway • Sirolimus, imiquimod, and thalidomide are being evaluated as therapies for KS KHALID M. GHARIB 30
  31. 31. Psoriasis • Angiogenesis is thought to play a role in the dilated vasculature of the papillary dermis in psoriasis • Sirolimus in combination with cyclosporine has been used to treat psoriasis • Other antiangiogenic agents are currently being studied as treatments for psoriasis KHALID M. GHARIB 31
  32. 32. KHALID M. GHARIB 32

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