Intro to the endothelium Flashcards
How much of heart is endothelial cells?
3:1 Endotheliam:CM
Why don’t endothelial cells become 3D structure?
Contact inhibition
Key property of endothelial cells
quiescent
I.e. not actively proliferating (average lifespan of an EC > 1 year)
Size of endothelial cell
1-2 μm thick and ~ 10-20 μm in diameter
What are endothelial cells?
A single layer of flat cells that line the entire vascular system (blood and lymphatic vessels)
Yolk cells become…
vascular
Inner become primary plexus to form yolk vasculature
Outer become blood cells
Embryo proper becomes..
vascular
Primary plexus differentiates into more specialised endothelial cells associated with artery and vein
from cardinal vein - lymphatic endothelial cells
Where do hematopoietic stem cells (HSC) originate from
Endothelium
- Specialised endothelium: hemogenic endothelium
Different transcription factors switched on/of
Which transcription factor switched on for endothelial to HSC transition?
Runx 1
Which transcription factor switched off for endothelial to HSC transition
HoxA3
Key marker for HSC
Runx1
Crucial marker for lymphatic endothelial cells and why
Prox1 because not found in other endothelial cells
Applications of tissue engineering of blood vessels
- Vascular graft for coronary and bypass surgery
- Vascular networks for organ regeneration
Endothelial cell heterogeneity
Not all EC in the body are the same: structural, functional, and genetic differences according to the position in the cardiovascular tree
Endothelial cell marker
(VWF, CD31, VE- Cadherin)
but there is no universal EC marker present exclusively in EC and in all EC
Permeability variations between endothelial cells
• Continuous, non-fenestrated: caveole system Tight junctions
• Continuous, fenestrated: discontinuous sinusoidal Found in filtration organs
Regulation of permeability, regulated by certain proteins
• Post capillary venules
Leucocyte trafficking
process is slightly different in
different types of endothelium and differing cell types → Stochastic switching of endothelial cells
What do endothelial cells regulate?
Permeability Inflammation Thrombosis and haemostasis Vascular tone Angiogenesis Leukocte transmigration
What do endothelial cells make?
Matrix products, adhesion molecules, inflammatory mediators Antithrombotic and procoagulant factors Vasodilator and vasoconstricting factors Growth factors KEY IS BALANCE
What is VE cadherin
Fundamental, cell-cell contract molecules
Ca2+ dependent adhesion molecule at endothelial adherens junctions
Role of VE cadherin
- Homophilic interaction with VE-Cadherin on opposite cells
• Inside the cell, binds to catenins to mediate interaction with actin cytoskeleton and signalling
• Regulates permeability, survival, shear stress and growth factors signals
Pathway of functions for VE cadherin
Wnt/b-catenin signalling
What modulates function of VE cadherin?
Phosphorylation
- disrupts junctions and and this increases permeability and leukocyte migration between endothelial cells
Basic b-catenin signalling pathway
- Two cells in contact, following angiogenesis
- β catenin is sequestered away with VE cadherin at the organised adherens junction
it is on the membrane and does not have an effect - When required (or in pathology) β catenin comes off from where it is being inhibited
- Goes into the nucleus
- To become a transcriptional cofactor
→ proliferation survival
VEGF control of endothelial haemostasis
Cell prolifertaion, survival, migration etc
Important pathway for stability of endothelium and vasculature
Angiopoietin-Tie2 ligand-receptor system
What is the Angiopoietin-Tie2 ligand-receptor system
- Ang-1 and Ang-2 are antagonistic ligands of the Tie2 receptor
- Ang-1 binding to Tie2 promotes vessel stability and inhibits inflammatory gene expression
- Ang-2 antagonises Ang-1 signalling, promotes vascular instability and VEGF-dependent angiogenesis
What is angiopoietin 1 synthesies by
pericytes found bound to vascular cells
Role of angipoietin 1
Binds to TIE2 receptor
- series of phosphorylation events
- inhibits NKkB = Anti-inflammatory
- activate pik3 = survival
- inhibit leukocyte recruitment by downregulation of adhesion molecules
Where does angiopoietin 2 come from
Weibel-palade bodies (formed from vWF) within endothelial cells
What does angiopoietin 2 do
Released from endothelial cells by inflammatory stimuli
- Antagonises binding of ang 1 to the TIE 2 receptor
- opposite effect of Ang1 -
Endothelial homeostasis
When is it diminished?
Inflammatory, proliferation, thrombotic
Balance of pro and anti factors
If there is constant activation of the endothelium E.g.. Constant inflammation stimulus, high LDL
The constant stimulation prevents the endothelium form switching back to the resting state and balance
Prolonged activation can be very detrimental
Signals that switch endothelium into pro-inflammatory state and what does it lead to
OxLDL High BP Smoking Viruses Mechanical stress High glucose Inflammation
Leads to ACTIVATION OF ENDOTHELIUM
what does activation of endothelium lead to?
Thrombosis
Permeability
Leukocyte recruitment
Angiogenesis
–> ATHEROSCLEROSIS
Pathogenesis of atherosclerosis
(1) Endothelial activation
Promotes increased permeability, leukocyte migration, etc.
(2) Leads to fatty streak formation Early lesion
Accumulation of fat and cholesterol
(3) Formation of an Advanced, Complicated Lesion of Atherosclerosis.
Leukocyte recruitment in normal conditions
Recruitment of blood leukocytes into tissues takes place normally during inflammation: leukocyte adhere to the endothelium of post-capillary venules and transmigrate into tissues
Leukocyte recruitment in atherosclerotic conditions
In atherosclerosis, leukocytes adhere to activated endothelium of large arteries and get stuck in the subendothelial space
Physiological role of leukocytes
normal immune surveillance and inflammation
Pathological role of leukocytes
Pathological role in chronic inflammatory diseases – atherosclerosis, rheumatoid arthritis, asthma, vasculitis, psoriasis
Recruitment of blood leukocytes into tissues takes place normally during inflammation: leukocyte adhere to the endothelium of post- capillary venules and transmigrate into tissues
• In atherosclerosis, leukocytes adhere to activated endothelium of large arteries and get stuck in the subendothelial space
• Newly formed post-capillary venules at the base of developing lesions provide a further portal for leukocyte entry
Angiogenesis and CV disease paradox
- Promotes atherosclerotic plaque growth and rupture
2. Therapeutic angiogenesis induces new vessel formation in ischemic tissues
