Angiogenesis pathogenesis

1. ANGIOGENESIS IN HEALTH
AND DISEASE
PRESENTER-DR. JAHNVI VIJAY
MODERATOR- DR. PANDURANGA
C

2. ANGIOGENESIS : A CURSE OR A
BOON?

3. LAYOUT
History
Introduction
Angiogenesis in embryo
Mechanism and types of angiogenesis
Angiogenesis in health
Angiogenesis in disease
Therapeutic angiogenesis - Use, Rationale and Limitations
Angiogenesis based treatments currently under clinical trials

4. HISTORY
• JOHN HUNTER provided the first recorded
scientific insights into the field of
angiogenesis.
• His observations suggested that
proportionality between vascularity and
metabolic requirements occurs in both health
and disease.

5. JUDAH FOLKMAN
Hypothesised and published in 1971 that the growth of a Tumor is angiogenesis-
dependent.

6. DEFINITION
VASCULOGENESIS-
Differentiation of precursor cells (angioblasts) into endothelial cells and the de novo
formation of a primitive vascular network
ANGIOGENESIS -
Angiogenesis is defined as the growth of new blood vessels from pre-existing blood
vessels.

7. WHAT IS ANGIOGENESIS?
• Occurs throughout life
• In both health and disease
• Begins in utero, continues through old age
• Changes in metabolic activity——> proportional changes in angiogenesis ——>
proportional changes in capillarity.

8. ANGIOGENESIS IN EMBRYO

9. STRUCTURE OF BLOOD
VESSELS
-

10. TYPES OF ANGIOGENESIS

11. SPROUTING ANGIOGENESIS
• Characterised by sprouts composed of endothelial cells
• Usually grow toward an angiogenic stimulus such as
VEGF-A.
• Can therefore add blood vessels to portions of tissues
previously devoid of blood
INTUSSUSCEPTIVE ANGIOGENESIS-
• Involves formation of blood vessels by a splitting process
• Here, elements of interstitial tissues invade existing
vessels.
• Form trans vascular tissue pillars that expand and form
new blood vessels
.

12. ACTIVATORS OF
ANGIOGENESIS
VEGF-A
FGF-2.
Angiopoietin- 1 and 2
PDGF
TGF-Beta

13. INHIBITORS
• ENDOSTATIN -Produced by proteolytic cleavage of collagen
• ANGIOSTATIN- Produced by proteolytic cleavage of plasminogen
• THROMBOSPONDIN-1(TSP-1)- Adhesive glycoprotein in matrix.

14. MECHANISMS OF ANGIOGENESIS
VEGF-A———Stimulates migration and proliferation of endothelial cells →Initiate
capillary sprouting in angiogenesis
———- Stimulates production of Nitric oxide → Formation of vascular lumen
FGF-2————- Stimulates proliferation of endothelial cells
Angiopoietin 1 and 2————Structural maturation of new blood vessels
PDGF- Recruit smooth muscle cells →Stabilise the new blood vessels
TGF-β —-suppresses endothelial proliferation and migration.enhances the production of
ECM proteins.

15. PROCESS OF ANGIOGENESIS
Following steps—
1. Vasodilation and increased permeability
2. Separation of pericytes and breakdown of the basement membrane
3. Migration of endothelial cells
4. Proliferation of endothelial cells
5. Remodeling
6. Recruitment of periendothelial cells
7. Suppression of endothelial proliferation

17. DELTA NOTCH SIGNALLING
PATHWAY
The NOTCH Signalling pathway regulates the sprouting and branching of new
vessels→Ensures new vessels that are formed have the proper spacing to effectively supply
the healing tissue with blood.
It is a cell–cell signaling system in which the ligand, Delta-like-4 matches with its notch
receptor on neighboring cells.
Both the receptor and ligand is cell bound and thus act only through cell–cell contact.
.

18. ANGIOGENESIS IN HEALTH
Capillaries grow and regress in healthy tissues according to functional demands.
1. EXERCISE-
Exercise stimulates angiogenesis in skeletal muscle and heart.
2. WEIGHT GAIN AND WEIGHT LOSS-
Capillaries grow in adipose tissue during weight gain
Capillaries regress during weight loss

19. ANGIOGENESIS IN DISEASE
CONDITIONS WHERE UNREGULATED ANGIOGENESIS IS SEEN-
Wound healing
Cancers
Ocular angiogenesis
Psoriasis
Rheumatoid arthritis
Nephropathy

20. 1. Wound healing and repair

21. 2.CANCERS
WHY TUMORS REQUIRES ANGIOGENESIS ?
• Tumors less than 1 mm3 receive oxygen and nutrients by diffusion from
host vasculature.
• Larger tumors require new vessel network.
• Tumor secretes angiogenic factors that stimulate migration, proliferation,
and neovessel formation by endothelial cells in adjacent established
vessels.
• Newly vascularized tumor no longer relies solely on diffusion from host
vasculature, facilitating progressive growth.

23. ANGIOGENIC SWITCH
• The ability of a tumor to induce the formation of a tumor
vasculature has been termed the ‘angiogenic switch’
• Can occur at different stages of the tumor-progression pathway
depending on the type of tumor and the environment.
• Acquisition of the angiogenic phenotype can result from genetic
changes or local environmental changes that lead to the activation
of endothelial cells.

24. STRUCTURE AND FUNCTION OF TUMOR VESSELS
• Chaotic architecture and heterogeneous blood flow that leads to
abnormal growth
• Excessively dilated blood vessels
• Extreme corkscrew like tortuosities
• Lack of pericyte support or abnormal pericytic function: Permeability
strongly increased -enlarged Junctions
• No functional lymphatics inside the tumor -enlarged in surrounding -
increases metastasis

25. Is there a Tumor graded on the basis of angiogenesis?
According to the 2016 WHO classification (Gliomas of astrocytic lineage)
WHO grade I- Pilocytic astrocytoma ( localised form)
WHO grade II tumors (diffuse astrocytoma): show only nuclear atypia
WHO grade III tumors (anaplastic astrocytoma): show nuclear atypia with focal
or dispersed anaplasia, significant proliferative activity and mitoses
WHO grade IV tumors (glioblastoma): show nuclear atypia, mitoses,
microvascular proliferation or necrosis

26. Microvascular proliferation:
◦ Hallmark of glioblastoma
◦ Glomerular tufts of mitotically active multilayered endothelial cells

27. 3. OCULAR ANGIOGENESIS
Visual impairment is attributed to angiogenesis in-
A. Retinopathy in diabetes
B. Sickle cell retinopathy
C. Retinopathy of prematurity
D. Retinal vascular occlusion
E. Age related macular degeneration (AMD)
F. Corneal graft rejection

28. Diabetic retinopathy

29. Age related macular degeneration
Choroidal neovascularisation occurs as a result of
hypoxia of overlying retinal pigment epithelial cells, due to
either thickening of Bruch’s membrane or to abnormalities
of choroidal perfusion, leading to the expression of pro-
angiogenic cytokines.

30. SICKLE CELL RETINOPATHY
• In sickle cell disease, Vaso-occlusion
occurs in most organs.
• Eye is one of the organs that gets
affected.
• Because of the occlusion, initial
angiogenic structures, buds or loop-like
new vessels, form at hairpin loops.
• Florid tufts of neovascularization called
sea fans, evolve later at these sites.

31. 4. Psoriasis
• Angiogenesis is not only a cofactor but also an inducer of psoriasis.
• Keratinocytes isolated from psoriatic skin show a strongly reduced
expression of thrombospondin-1 (TSP-1).

32. Role of angiogenesis in the pathogenesis of psoriasis

33. 5. Rheumatoid arthritis
A consequence of the synovial hyperplasia associated with RA is an increase in the distance between the
proliferating cells and the nearest blood vessels. This results in hypoxia and hypoperfusion and so the
augmented proliferation of blood vessels.

34. 6. Nephropathy
Mechanism and pathogenic role of abnormal angiogenesis in diabetic nephropathy

35. The upregulation of VEGF-A in early stages of diabetic nephropathy
may provide a mechanism for the initial progression of the disease,
leading to excessive blood vessel formation.
The decline of VEGF-A in the later phase of diabetic nephropathy may
reflect a loss of endogenous VEGF-A due to the disruption of
podocytes and tubular cells in chronic kidney damage

36. THERAPEUTIC ANGIOGENESIS
1. Tissue remodelling
• Recently, stem cell derived vascular cells or endothelial progenitor cells
(EPCs) have been found to be beneficial because of their capability for
vasculogenesis.
• In adults, these endothelial precursors are derived primarily from bone
marrow.
• These precursors, may have no or little contribution physiologically in an
adult, but are found to be promising in organ repair and tissue remodelling
and promoting tumour growth.

37. 2. Wound healing
• Formation of new blood vessels provides a route for oxygen and nutrient delivery
• Also acts as a conduit for components of the inflammatory response during the
healing of wounds.
• Pro-angiogenic treatments have shown remarkable improvement in the healing of
wounds in pathological conditions.
• Topical use of VEGF ,VEGF gene transfer might be a new approach to treat wound
healing disorders associated with diabetes.
• Also, recombinant platelet derived growth factor-BB (rhPDGF-BB) has been
approved to treat diabetic neuropathic foot ulcers.

38. 3. Cardiovascular diseases
ATHEROSCLEROSIS
• Role of angiogenesis in atherosclerosis is both adaptive and pathological.
• In early atherosclerosis- Angiogenesis prevents ischemia by promoting
neoangiogenesis from the adventitial vasa vasorum.
• But in advanced atherosclerosis- Chronic inflammation further promotes
angiogenesis, but these capillaries are leaky and easily susceptible to injury by
cytotoxic agents produced inside the plaque. Hence, it plays a role in plaque growth,
intraplaque haemorrhages, cholesterols crystal formations within the plaque, plaque
destabilization and thromboembolic events.

39. ISCHEMIC HEART DISEASE
• Coronary collaterals develop.
• They limit myocardial ischemia during coronary occlusion.
• Well-developed coronary collaterals may minimize the infarct area
• Help protect the myocardium from infarction during episodes of ischemia
• May extend the limited number of valuable “golden hours” from the onset of an acute
myocardial infarct to successful coronary reperfusion.

40. RATIONALE FOR ANGIOGENESIS
BASED TREATMENTS IN CANCER
Some of the major advantages of angiogenesis based treatment over others are:
1. A single vessel provides the nutrition for thousands of tumour cells and has to be
damaged at only one point to block blood flow upstream and downstream.
2. The endothelial cell is a normal diploid cell, which is unlikely to acquire genetic
mutations that render it drug resistant.
3. Temporary effects on vascular function may be sufficient to kill the endothelial cells

41. LIMITATIONS OF ANGIOGENESIS
BASED TREATMENTS
Most of the angiogenesis based treatments have worked in experimental rodent
models but have not been successful in clinical trials.
1. First of all, antiangiogenesis treatments target actively proliferating endothelial
cells. However, the relative number of proliferating EC is far smaller in human
tumours than in rodent tumour models.
2. Multiple growth factors, receptors, and other components of the microenvironment
support angiogenesis. Therefore, treatment targeted to a single factor may not be
completely effective

42. 3. Vasculature is tissue and tumour type specific. Moreover, vascular mimicry—where
the tumour vasculature presents genomic and phenotypic similarities with that of the
tumour cells—makes the tumour microvasculature more unpredictable.
4. The drug delivery to the ischaemic site can be a major limiting factor, specifically
without any tools to monitor the site specific drug availability within the tumour.
5. Monitor the antiangiogenic response in the patients is difficult.
6. Angiogenesis based treatment is found to be more effective in small tumours than
advanced cancers.

43. FOOD AND DRUG ADMINISTRATION (FDA)
APPROVED ANGIOGENESIS BASED TREATMENTS
1. Bevacizumab(called Avastin) is the first approved anticancer agent developed on
angiogenesis based treatment. Bevacizumab is a recombinant humanised
monoclonal antibody directed against VEGF.
2. Regranex 0.01% (recombinant platelet derived growth factor-BB) is approved by
FDA for the treatment of diabetic neuropathic foot ulcers.

44. OTHER PROMISING ANGIOGENESIS
BASED TREATMENTS
1. GENE THERAPY
• In patients with retinal neovascular disease, the high systemic doses required to
achieve therapeutic intraocular levels would be expensive and hazardous, because
of the blood-retinal barrier.
• In contrast, gene treatment provides the possibility of localised, targeted, sustained
delivery of therapeutic proteins into an appropriate intraocular site.
• Inhibition of VEGF by local gene transfer of its soluble receptor sFlt-1 reduces
neovascularisation.

45. 2. INHIBITORS OF HIF
• HIF is an αβ- heterodimer
• Among the isoforms of HIF-α, HIF-1α and HIF-2α are more closely related with
hypoxia response.
• Recently, small molecule inhibitors of the HIF hydroxylases are being used in
treatment. For example- FG0041 (under trial).

46. 3. COMBINATION THERAPY
• Tumours become self reliant but are still nurtured by the blood vessels
• Therefore targeting both the vessel as well as the tumour cells may be a
reasonable strategy.
1. IN CHEMOTHERAPY- Recombinant proteins together with chemotherapy
yielded a potent anticancer effect in ovarian and pancreatic cancer models.

47. 2. IN RADIOTHERAPY- Radiation can damage the tumour cells within the centre of
the tumour, but can upregulate hypoxia inducible factor, which can increase the
expression of VEGF.
The combination of antiangiogenic drugs and radiation has been shown to have
potent antitumour effects.
During this treatment modality, angiogenesis based drugs may work as radiation
sensitisers, facilitating the entrance of radiation into the tumour.
Anti-VEGF treatment can potentiate radiation therapy as well as decrease
resistance of tumour cells.

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