Intro to the endothelium Flashcards by Mridul Rana

How much of heart is endothelial cells?

3:1 Endotheliam:CM

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Why don’t endothelial cells become 3D structure?

Contact inhibition

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Key property of endothelial cells

quiescent

I.e. not actively proliferating (average lifespan of an EC > 1 year)

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Size of endothelial cell

1-2 μm thick and ~ 10-20 μm in diameter

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What are endothelial cells?

A single layer of flat cells that line the entire vascular system (blood and lymphatic vessels)

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Yolk cells become…

vascular

Inner become primary plexus to form yolk vasculature

Outer become blood cells

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Embryo proper becomes..

vascular

Primary plexus differentiates into more specialised endothelial cells associated with artery and vein
from cardinal vein - lymphatic endothelial cells

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Where do hematopoietic stem cells (HSC) originate from

Endothelium
- Specialised endothelium: hemogenic endothelium
Different transcription factors switched on/of

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Which transcription factor switched on for endothelial to HSC transition?

Runx 1

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Which transcription factor switched off for endothelial to HSC transition

HoxA3

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Key marker for HSC

Runx1

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Crucial marker for lymphatic endothelial cells and why

Prox1 because not found in other endothelial cells

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Applications of tissue engineering of blood vessels

Vascular graft for coronary and bypass surgery

- Vascular networks for organ regeneration

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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

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Endothelial cell marker

(VWF, CD31, VE- Cadherin)

but there is no universal EC marker present exclusively in EC and in all EC

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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

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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

1. Promotes atherosclerotic plaque growth and rupture | 2. Therapeutic angiogenesis induces new vessel formation in ischemic tissues