Endothelium Flashcards
Where is the endothelium found?
A thin monolayer of endothelial cells around found in the inner layer of blood vessels
Blood vessel composition:
Endothelium
Smooth muscle cell
Elastic/connective tissue
What does the endothelium do?
Produces molecules that are used in dependent vasodilation, antithrombotic, anti-inflammatory, anticoagulant/prothrombotic and antihypertrophic
Example - nitrix oxide
It works synergistically with the smooth muscle cells - to thelp maintain arterial pressure
Describe the endothelium’s function in health?
Nitric oxide is synthesised by the endothelium
It dilates blood vessels
It reduces platelet stickiness
Reduces monocyte stickiness - preventing the formation of plaque
Reduces multiplication (out of control) of smooth muscle cells of the artery wall
Reduces release of superoxide radicals
Reduces oxidation of LDL cholesterol (major component of plaque)
Describe the endothelial diversity?
Different endothelial origins or environments may influence vascular physiology control i.e. in different vessels or regions of the body
The endothelial cell is an input-output device
Responds to different surroundings, environments and changes
Responds to both biochemical and mechanical changes
What are the different phenotypes of the endothelium within the vessels?
Capillary:
Continuous not perforated - skin, lung, heart
Continuous perforated - endocrine glands, GI mucosa, glomerulus
Discontinuous/sinusoidal - liver
Post-capillary venule
Lumen - small intercellular cleft
During inflammation - widening of the intercellular cleft, allowing fluids and solutes to enter
What is involved in the input-output activity of the endothelium?
Cell adhesion
Response to growth factors
Interaction with migrating cells
Balance between dormancy, proliferation and death
Depends on the input to the role it plays
What are some key physiological features the endothelium exhibits?
De novo blood vessel network formation (vasculogenesis)
New blood vessel sprouting (angiogenesis)
Vascular homeostasis e.g. blood pressure control
Blood clotting
Disease related functions and dysfunction
Describe endothalial cell adhesion?
Endothelial cells have key adhesive functions:
Provision of an intercellular barrier
Regulation movement of molecules
Regulation of cell movement
Endothelial barrier function regulates angiogenesis and vasculogenesis
Give an example of endothelial adhesion?
Interaction between endothelial cell and leukocytes are essential for inflammatory processes
Leukocytes become activated and transmigrate between the endothelial cells into surrounding tissue
Here in the surrounding tissue the inflammatory response can begin
Describe the balance the endothelium is trying to regulate?
Dilation, growth inhibition, antithrombosis, anti-inflammation
Constriction, growth promotion, pro-thrombosis, pro-inflammation
At any one time they are trying to regulate
Describe angiogenesis?
The endothelium cells form new blood vessels that sprout from it
How is angiogenesis linked to cancer?
Innervation of solid tumour with leaky blood vessels
Solid tumour growth depends on angiogenesis
Spread of tumour cells via the vascular network to other sites (metastasis)
What stimulates angiogenesis?
Hypoxia
Low (<1%) oxygen = hypoxia linked to sold tumour growth and spread
Hypoxia-regulated synthesis of pro-angiogenic factors
Hypoxia stimulates pro-angiogenic VEGF-A synthesis
VEGF-A secretion stimulates angiogenesis
VEGF-A is dependent on HIF-1 activity
VEGF-A is secreted and binds to cognate receptors on the endothelium
Blocking such interactions can be used to treat cancer e.g. Avastin and Sutent
Describe HIF-1 proteins
HIF protein complexes regulate gene transcription e.g. VEGFA locus
HIF-1a subunits undergo, ubiquitination for degradation in high oxygen (>1% O2)
HIF-1b subunit is stable
HIF subunits have gene expression regulatory properties
HIF’s are used in oxygen regulation of multiple vascular responses and disease states
What describes the surfaces of the endothelial cell?
Endothelial Glycocalyx
This is a carbohydrate-rich layer lining the vascular endothelium
It is connected to the endothelium through several “backbone” molecules:
Cell surface glycoproteins
Glycolipids
Proteoglycans
Responds to different substances in blood and other fluids
What are some receptors in the endothelial glycocalyx?
Vascular endothelial growth factor (VEGF) receptors
They are a type of tyrosine receptor kinases (TRK)
There are 3 receptors 1-3
There are 5 VEGF’s A-E
Multiple splice variants encoded by each gene - they can bind to various receptors for different cellular responses
VEGF-A is the most important as it is closely associated with tumour growth and progression
What is involved in angiogenesis regulation?
Blood vessel sprouts express Dll4 (ligand for Notch)
Stalk cells express unique cell surface receptors - Notch and VEGFR2
VEGFR2 signalling positively regulates angiogenesis
Notch signalling negatively regulates angiogenesis
Describe the endothelial adhesion interaction with leukocytes?
Leukocyte adhesion-cascade:
This uses many cells and molecules - the movement of white blood cells
Capture of the leukocyte on the endothelial cell
Selectins- bind sialyl-LewisX sugars, found on eg PSLG-, low affinity, transient in nature
They signal via phosphoinositide-3-kinase(gamma) (PIK(gamma)) resulting in slow rolling along the endothelial layer
Activation through many molecules
Arrest - leukocyte stops rolling (mediated by integrins)
Adhesion is then strengthened by spreading
Then intravascular crawling where paracellular and transcellular transmigration takes place
(Leukocyte squeezes through the endothlial layer) - moving into the extra cellular matrix
Describe atherosclerosis and the role of the endothelium?
Atherosclerosis: Plaques or lesions Fat-filled streaks or lesions Major artery blockage by blood clots Causes heart attacks or strokes
Monocytes are a type of leukocyte which bind to the endothelium
Monocytes differentiate into macrophages which bind modified LDLs
Fat and lipid-filled macrophages become foam cells that die
Atherosclerotic plaque lesion starts to appear in the blood vessel wall
This leads to atherosclerotic plaque rupture
Describe endothelial cell differentiation?
Endothelial cells are derived from stem cells
Differentiation pathway during normal development
Can be derived from circulating stem cells during adult life
Provides potential in therapy
They have different markers that we can follow
Describe endothalial stem cell therapy?
Isolation of circulating Endothelial Progenitor Cells (EPCs)
Differentiation in vitro to ECs (in the test tube or lab)
Re-implantation of differentiated cells into damaged tissue in vivo e.g. damaged heart or blood vessel tissues
What are endothelial derived tumours?
Kaposi’s Sarcoma Herpes Virus (KSHV) Linked to HIV infection Infects endothelial cells Promotes endothelial growth and immortalisation Forms metastatic tumours
KSHV encoded gene mediates endothelial cell transformation
Viral GPCR
Blocks cell death
Elevates signalling and expression of pro-survival/proliferative growth factors
