Vascular Endothelium - In Health and Disease Flashcards
What are the 3 main layers of the vascular endothelium?
- Tunica adventitia
- Tunica media
- Tunia intima
What is found within the tunica adventitia (2)?
- Vaso vasorum
- Nerves
Nerves
Which types of fibres form the tunica media (2)?
- Smooth muscle cells
- Elastic fibres
What is the tunica intima?
- Endothelium
Which cells support the venule and capillary endothelium?
- Mural cells (pericytes)
What surrounds the capillary (2)?
- Basement membrane
- Pericapillary cells (pericytes)
What is the function of the mural cells (pericytes)?
- Maintains homeostatic & haemostatic function
What is endothelial heterogeneity?
- Endothelial cells and microvasculature have organotypic (tissue specific) properties and expression profiles
The endothelial phenotype is dependent on location.
Which types of proteins are involved in cell adhesion and the formation of the monolayer?
E-cadherins
Which process arrests cell growth when cells come in contact with each other?
- Contact inhibition
What are the 3 types of endothelium?
- Fenestrated continuous endothelium
- Non-fenestrated continuous endothelium
- Discontinuous
Where are fenestrated continuous endothelium found (2)?
- Kidney glomerulus
- Gastrointestinal tract
To facilitate filtration and absorption
Where are the non-fenestrated continuous endothelium found (4)?
- Muscle
- Lung
- Skin
- Blood brain barrier
To regulate diffusion
What type of endothelium is found within the liver?
- Discontinuous
What type of layer is formed by the endothelium?
- Monolayer
What are the main functions of the microvascular endothelium? (6)
- Release angiocrine factors
- Regulate permeability of vessels
- Regulate immune response
- Angiogenesis
- Vascular tone
- Haemostasis and thrombosis
Which factor is secreted by the endothelium and mediates platelet adhesion?
- Von Willebrand Factor
What is the resting equilibrium in endothelial cells?
A balance between:
* Anti-inflammatory
* Anti-thrombotic
* Anti-proliferative factors
VS
* Pro-inflammatory
* Pro-thrombotic
* Pro-angiogenic factors
Describe the proliferation rate in endothelial cells
- Low proliferation rate unless angiogenesis is induced
What factors contribute towards endothelial cell dysfunction (10 / know 5)?
- Hyperchoelsterolemia
- Diabetes mellitus / metabolic syndrom
- Hypertension
- Sex-hormonal imbalance
- Ageing
- Oxidative stress
- Pro-inflammatory cytokines
- Infectious agents
- Environmental toxins
- Haemodynamic forces
Which factors activate the endothelium (7)?
- OxLDL
- High glucose
- High blood pressure
- Inflammation
- Mechanical stress
- Viruses
- Smoking
What are the responses of the activated endothelium (4)?
- Thrombosis
- Senescence
- Permeability
- Leukocyte recruitment
Senescence: loss of a cell’s power of division and growth
What is a marker of endothelial injury?
Circulating endothelial cells
What are the matrix products involved in angiogenesis (5)?
- Fibronectin
- Laminin
- Collagen
- Proteoglycans
- Proteases
What are the growth factors concerned with angiogenesis (3)?
- Insulin-like growth factor
- Transforming growth factor
- Colony stimulating factor
Which adhesion molecules exist on the endothelium and promote neutrophil migration?
- Intercellular adhesion molecule (ICAM)
- Vascular cell adhesion molecule (VCAM)
Selectins - P-selectin
Which inflammatory mediators are secreted by the endothelium (5)?
- IL-1
- IL-6
- IL-8
- Leukotrienes
- MHC-II
What are the vasoconstricting factors released by the endothelium (5)?
- Angiotensin-Converting Enzymes (ACE)
- Thromboxane A2
- Leukotrienes
- Free radicals
- Endothelin
Which type of factor is endothelin?
- Vasoconstricting factor
Which type of factor is thromboxane A2?
- Vasoconstricting factor
What are the 2 vasodilator factors released by the endothelium?
- Nitric oxide
- Prostacyclin
What are the procoagulant factors that are released by the endothelium (6)?
- Von Willebrand factor
- Thromboxane A2
- Thromboplastin
- Factor V
- Platelet activating factor
- Plasminogen activator inhibitor
What are the anti-thrombotic factors released by the endothelium (4)?
- Prostacyclin
- Thrombomodulin
- Antithrombin
- PA heparin
What are the four stages of the pathogenesis of atherosclerosis?
- Leukocyte recruitment
- Permeability
- Shear stress
- Angiogenesis
What is the first step of the pathogenesis of atherosclerosis?
- Increased endothelial permeability to lipoproteins and plasma constituents mediated by nitric oxide, prostacyclin, platelet derived growth factor and endothelin.
Fatty streak accumulation within the tunica media induces a fibrotic repair process forming what?
- A fibrous cap
What is ultimately formed due to foam cell formation within the tunica media?
- A necrotic core formed from leukocytes , lipids and debris
What does the necrotic core represent (3)?
- Represents the results of apoptosis and necrosis, increased proteolytic activity and lipid accumulation
Which molecules are upregulated by endothelial cells that promote leukocyte adhesion (2)?
- E-selectin
- P-selectin
Which molecules are upregulated by leukocytes that promote adhesion to the endothelium (3)?
- L-selectin
- Intregrins
- Platelet endothelial cell adhesion molecule
Which molecules promote the migration of leukocytes into the artery wall (5)?
- Low-density lipoprotein (LDL)
- MCP-I
- IL-8
- Osteopontin
- M-CSF
The phagocytosis of OxLDLs by macrophages forms what type of cell?
- Foam cell
Which molecules are released by macrophages which oxidise LDLs?
- Free oxygen radicals
Which factors promote macrophage migration into the sub-endothelium (3)?
- MCP-I
- MCSF
- Oxidised low density lipoprotein (OxLDL)
What is diapedesis?
- The movement of neutrophils from the circulation into the tissues
What are the first stages of neutrophil migration?
- Rolling and adhesion occurs as neutrophils establish reversible binding between selectins on the endothelial surface and carbohydrate ligands
Which inflammatory cell releases IL-8?
Macrophage
What are the functions of IL-8?
- Chemoattractant of neutrophils
- Upregulates endothelial adhesion molecules (selectins)
Which chemokine promotes neutrophil migration?
- IL-8
Which tight adhesive molecules are found on neutrophils and interact with the endothelium?
MAC-I
LFA-I
Which tight adhesive molecules are found on the endothelium to interact with migrating neutrophils (2)?
- ICAM-I
- 2 ligands
Which molecules foster transcellular interactions for neutrophils?
- Platelet endothelial cell adhesion molecule (PECAM)
- Junctional adhesion molecule (JAM)
Where does the majority of leukocyte transmigration occur?
- Post-capillary venules
Which CD marker is produced by endothelial cells and contribute to diapedesis?
Diapedesis: The movement of neutrophils from the circulation into the tissues
- CD99
What is the function of CD99?
- Upregulates laminin binding integrin
How do neutrophils transmigrate into tissues?
- Infiltrating neutrophils disrupt the interaction of junctional adhesion molecules (JAM) and vascular endothelial cadherins
- Neutrophils display motility involving membrane protrusions and the rearrangement of the cytoskeleton of pseudopodia
- Mediated by latelet endothelial cell adhesion molecule (PECAM) interactions on both cells
Where do leukocytes transmigrate into (2)?
- Tunica intima
AND
- Subendothelial space
What is found in the subendothelial space that assisst leukocyte migration?
Extracellular matrix of proteoglycans and lipids
What is the effect of increasing endothelial permeability in the pathogenesis of atherosclerosis (2)?
- Lipoproteins pass through the fenestrations into the subendothelial space
- Macrophages transmigrate into the subendothelial space, detecting LDLs via scavenger receptors
Which type of macrophage receptors detect lipoproteins?
- Scavenger receptors
What forms foam cells?
- Oxidised lipoproteins phagocytosed by macrophages
Which areas potentiate atheroma formation (2)?
- Curvatures
- Bifurcations
Ascending aorta and the aortic bifurcation of the abdominal aorta
Result in non-uniform haemodynamic forces, potentiating the probability of atheroma formation
How do plaques affect shear stress?
- Narrows the arterial lumen disrupting the laminar flow, thus blood flows in a turbulent manner reducing shear stress that is exerted onto the vascular endothelial cells
- Disturbing the homeostatic balance that ultimately leads to thrombosis and inflammation
What is laminar flow?
- Blood flows in discrete current lines with minimal interference with each other
What are the 3 characteristics of laminar flow?
- Velocity is constant at any one point, flowing in layers
- Blood flows fastest at the centre of flow
- Wall shear stress exerted on the endothelium is high and directional
When is shear stress high on the endothelium?
- During laminar flow
What happens to shear stress during turbulent flow?
- Blood flow is distributed with nonuniform and irregular distribution of low wall shear stress
What does laminar flow promote in the endothelium (3)?
- Endothelial survival
- Inhibition of Smooth Muscle Cell proliferation
- Nitric oxide (NO) production (Vasodilator)
What happens to nitric oxide production in turbulent flow?
- Decreases NO production
What happens to smooth muscles in turbulent flow?
- Smooth muscle cell proliferation
Proliferation: rapid reproduction of a cell, part, or organism
What type of environment is maintained by laminar flow?
- High shear stress exerted onto the endothelium by laminar flows maintains an anti-thrombotic and anti-inflammatory environment
What does turbulent flow promote in the endothelium (5)?
- Thrombosis, inflammation (leukocyte adhesion)
- Endothelial apoptosis
- Smooth Muscle Cell proliferation
- Loss of Nitric oxide (NO) production
What is the function of nitric oxide released by endothelial cells on lipoproteins?
- NO reduces the oxidation of LDL cholesterol (major component of plaque)
What effect is exerted by NO on platelets?
- Anti-thrombotic, reduces platelet activation.
What effect does NO have on the vessels?
- Dilation of blood vessels
What effect does NO have on superoxides?
- NO reduces the release of superoxide radicals from macrophages and neutrophils
What are the 6 main functions of nitric oxide?
- Reduces platelet activation (Anti-thrombotic)
- Reduces release of superoxide radicals from macrophages and neutrophils
- Dilates blood vessels
- Reduces proliferation of smooth muscle cell within the tunica media
- Inhibits monocyte adhesion
- Reduces oxidation of LDL cholesterol
What is the janus paradox in angiogenesis?
- Angiogenesis within the vaso vasorum of the adventitia promotes plaque formation
Vs
- Revascularisation uses the principle of angiogenesis for therapeutic treatment of post-ischaemic coronary arteries
Which factor stimulates angiogenesis in hypoxic conditions?
- Hypoxia inducible factor stimualtes epo production and potentiates activity of angiogenesis
What are the benefits of angiogenesis (3)?
- Embryonic development
- Menstural cycle
- Wound healing
What is the therapeutic treatment of post-ischaemic coronary arteries?
- Revascularisation