1- Angiogenesis and Vasculogenesis Flashcards
Overview of angiogenesis
- angiogenesis and vasculogenesis
- angiogenic cytokines
- role of cytokines in vasculogenesis and
angiogenesis
-Tumor angiogenesis
General concepts of angiogenesis
1- Low turnover but entere active proliferation
2- Linked to pathological processes ( proliferative, tissue repair, ischemia)
3- Regulated by the mechanism that regulate formation of new blood vessels in the embryo
4- A multifactorial phenomenon in steps
What is angiogenesis?
The formation of a new vessel from pre-existing vessel
When does angiogenesis occur?
Physiological conditions:
1- Embryogenesis and fetal development
2- Endometrial regeneration
Pathological conditions:
1- Wound healing
2- Autoimmune and inflammatory pathologies
3- Tumors
Why does agiogenesis occur?
Lack of O2 diffusion that lead to hypoxia which in term lead to apoptosis
What are the different types of angiogenesis?
Sprouting angiogenesis and splitting angiogenesis
What is Sprouting angiogenesis
The first identified form of angiogenesis.
The process:
1- Biological signals known as angiogenic growth factors activate receptors on endothelial cells present in pre existing veins
2- The activated endothelial cells begin to release enzymes called proteases that degrade the basement membrane in order to allow endothelial cells to escape from the original (parent ) vessel wall
What is splitting angiogenesis?
1- Called intussusception
2- The capillary wall extends into the lumen to split single vessels into two.
3- Intussusception is important becasue it is a reorganization of existing cells. It allows a vast increase in the number of capillaries without a corresponding increase in number of endothelial cells. Especially important in embryonic development as there are not enough resources to create a rich microvasculature with new cells every time a new vessel develops.
Modern terminology of angiognesis
1- Vasculogenesis
2- Angiogensis
3- Arteriogenesis
Define vasculogensis
Formation of vascular structures from circulating or
tissue-resident endothelial stem cells(angioblasts), which proliferate into
de novo endothelial cells. This form particularly relates to the embryonal
development of the vascular system
Define angiogenesis
Formation of thin-walled endothelium-lined structures
with /without muscular smooth muscle wall and pericytes (fibrocytes).
This form plays an important role during the adult life span, also as
“repair mechanism” of damaged tissues
Arteriogenesis
Formation of medium-sized blood vessels possessing
tunica media plus adventitia.
What is and when does vasculogenesis occur?
Formation of vessels by differentiation of cells from angioblasts
In the embryo: formation of a primitive tubular network
In the adult: differentiation and proliferation of endothelial cells in a non-
vascularized tissue
Organization of Vasculo -, angio- and arterio- genesis
Vasculogenesis: endothelial precursors are assembled to form a network of tiny blood vessels (vascular
plexus) where you can already distinguish between arteries and veins.
Angiogenesis: plexus expands to form an organized network of vessels that branch out gradually.
Arteriogenesis: The vessels are covered by pericytes (PC) and smooth muscle cells (SMC) that allow the
vessels to regulate the blood flow.
Lymphangiogenesis: the lymphatic system develops from veins.
How does sprouting occur?
When there is less O2, there are high Hypoxia inducing factor (HIF) allowing the secretion of VEGF.
A growing sprout is composed of :
1- Tip cell - upregulate DII4, VEGFR3, VEGFR2
2- Stalk cells _ upreglate Notch1 and Jagged 1
3- Phalanx cells - upregulate VE-Cadherin , VEGFR1
Angiogenic cytokines - VEGF-A
as a protein
1- Family members: VEGF, VEGF-B, VEGF-C, PIGF
2- Dimeric glycoprotein with multiple isoform
3- Targeted mutations in VEGF resulted in defective vasculogenesis and angiogenesis
Angiogenic cytokines - VEGF-A
production
1- Expressed at low levels in a variety of adult tissues and at higher levels in a few sites, such as podocytes in the glomerulus and cardiac myocytes
Angiogenic cytokines - VEGF-A
inducing agents
1- Hypoxia
2- TGF-B
3- PDGF
4- TGF-A
Angiogenic cytokines - VEGF-A
receptors
1- TKR seven ig-like domains in the extracellular portion.
2- One transmembrane domain
3 - On eintracellular tyrosin kinase sequence
4- Expressions:
1. VEGFR1 and R2- Blood vessels
2. VEGFR3: Lymphatic cells
( restricted to endothelial cells)
5- Functions:
- VEGFR2- mediates proliferation, migration
- VEGFR-1- does not mediate inhibitory role (decoy receptor for VEGF)
- Soluble VEGFR-1: isoform of alternative splicing that works as a decoy
Angiogenic cytokines - VEGF-A
overall function
1- Promotes angiogenesis
2- Increase vascualr permeability
3- Stimulates endothelial cell migration
4- Stimulates endothelial cell proliferation
5- VEGF-C selectively induces hyperplasia of lymphatic vasculature
6- Up-regulates endothelial expression of plasminogen activator, plasminogen activator inhibitor-1a, tissue factor and interstitial collagenase
Angiogenic cytokines - Angiopoietins
Functions
Ang-1 and Ang-2 binds to the receptor Tie2
Ang-1: constitutively expressed by pericytes and vascular smooth muscle cells
promotes vessel integrity, inhibits vascular leakage and suppresses inflammatory gene expression
Ang-2: stored in Weibel–Palade bodies and rapidly secreted and induced upon stimulation
works as an antagonist of Tie2 inhibiting its protective signalling, blocks Tie 2 protective signalling
Role of cytokines in vasculogenesis
1) VEGF binds to VEGF receptor-R2 present on mesangioblast and induces its endothelial differentiation and its proliferation. Knock-out mice for
VEGFR2 die on Day 8 of embryonic life and have no
endothelial cells
2) The capillary tube formation occurs when VEGF binds to VEGF-R1. Knock-out mice for VEGFR1 dies on Day 8 of embryonic life due to the lack of vessels.
3) Ang-1 binds to Tie2 and allows the recruitment of pericytes and smooth muscle cells that maintain the stability of the vessel.In the Tie2 knockout mouse vessels are formed, but they break quickly. Death at 9-10 days of embryonic life.
4) Ang1 and TGFb: stabilize the nascent vessels
5) Ang2: destabilizes blood vessels (angiogenesis or regression)
Angiogenesis in pathology
The balance between pro-and anti-angiogenic factors is
altered in favor of angiogenesis in various diseases: it is
called angiogenic switch
Tumors Psoriasis Inflammatory diseases (arthritis ...) diabetic retinopathy Hemangiomas
how does angiogenesis control tumor growth
• Tumor can stay in a ‘dormant’ state for
long periods.
• The angiogenic switch allows for growth of
the tumor to occur.
• Increased angiogenesis correlates with
worse prognosis.
Explain the growth of tumor vessels
1- Sprouting
2- Intussusceptive growth
3- Incorporation of BM-deerived precursors
4- Cooption of existing vessels
VSP inhibitors and TKIs
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1- Bevacizumab (Anti-VEGF)
2- Afliberecept (VEGF Trap)
3- Ramucirumab (Anti-VEGFR2)
and TKIs
