Endothelium Flashcards
What is the endothelium?
Lines all blood and lymphatic vessels.
It is a large endocrine gland.
Majority of endothelial cells are present within microvasculature/ capillaries.
What is the activity of endothelial cells?
Don’t turnover quickly.
Mainly quiescent
If injured, can rapidly divide to repopulate damaged tissues and regenerate blood vessels.
What is the distribution of endothelial cells in the vasculature?
Most cells are in the capillaries for transportation of substances in and out of blood.
Some in post-capillary venules for inflammation.
Some in arterioles and arteries for blood distribution.
What is endothelial cell important for?
Allowed the study of endothelial function in isolation:
Migration
Permeability
Proliferation
Survival
Angiogenesis - tube formation and sprouting assays.
What is vasculogenesis?
The in situ differentiation of endothelial cells from precursor cells.
This is the first stage of development, then the rest of the vasculature develops from existing vessels by angiogenesis.
How do the endothelial cells form?
The mesoderm differentiates to form a hemangioblast precursor.
The endothelial cells then form first from this, then form hemogenic endothelium, which then gives rise to hematopoietic stem cells.
What is the process of vessel development?
Vasculogenesis - endothelial cells form blood islands, which fuse together to form a primary capillary plexus.
Angiogenesis - the plexus is remodelled to form a vascular network.
Lymph angiogenesis - sprouting of lymphatics from the veins.
Angioblasts also assemble into the larger vessels.
What is the maturation of vessels?
Simple capillaries are formed from only endothelial cells in a tube.
The majority of capillaries have accessory cells that support the capillaries - pericytes, basement membrane, smooth muscle cells and fibroblasts.
Large vessels have an intima, media and adventitia.
What is phenotypic heterogeneity?
Allows endothelium to conform to the diverse needs of underlying tissues throughout the body.
Allows adaptation to diverse microenvironments.
e.g. hypoxic hyperosmolar environment of the medulla of the kidneys compared to the well-oxygenated pulmonary alveoli.
How is the endothelium arranged in arteries?
Endothelial cells are aligned in the direction of undisturbed flow.
The cells are long and narrow.
The endothelium is continuous with many tight junctions.
How is the endothelium arranged in veins?
The endothelial cells are not aligned in the direction of blood flow.
The cells are shorter and wider.
The endothelium is continuous.
How do epigenetics cause endothelial cell heterogeneity?
Epigenetic changes are passed on through cell division and are more resistant to changes in the microenvironment.
e.g. methylation and acetylation changes which genes are upregulated.
How does the local environment cause endothelial cell heterogeneity?
Local environment cues such as the cytokines and oxygen levels determine a lot of the phenotype of endothelium, influence receptor signalling and gene expression.
Cues must be maintained and are not passed on by mitosis.
What is the function of the endothelium?
Regulates vascular homeostasis.
Acts as a sensor and an effector.
Barrier function/ permeability
Blood flow regulation
Haemostasis
Leukocyte recruitment
Hormone trafficking
What is the endothelial barrier function?
The endothelium is the main barrier to the escape of substances from the blood to the tissues.
It is selective - specialised in different regions of the body based on function.
What is the majority of endothelium?
Most vessels have non-fenestrated continuous endothelium e.g. arteries, veins, brain capillaries, skin and heart.
In the kidneys though, it is fenestrated for filtration.
In the liver, which is adapted for transport, it is sinusoidal, discontinuous, and cells are not closely opposed.
What is the endothelial basement membrane?
Cells are polarised - there is distinct expression of receptors on the apical and basal sides.
The endothelial basal membrane sits on a thick basement membrane and is associated with ECM - containing collagen, fibronectin and laminin.
What are the types of endothelial intercellular junctions?
Junctions are tighter on the arterial side and looser on the post-capillary venules.
Adherens and tight junctions are the main barrier to paracellular transport.
Adherens have VE cadherin.
Tight junctions have claudins and occludins and JAMs.
Connexins/gap junctions are for communication between cells.
What are endothelial cell junctions?
Endothelial cells have a homotypic interaction of junctional proteins which binds the cells to each other, and proteins and integrin link the cells to the cytoskeleton.
This is important for signalling stresses of the cells e.g. shear stress, blood flow over top, haemodynamics.
What is the type of transport in continuous endothelium?
Paracellular transport of water and small molecules through intercellular clefts.
Transcytosis - moves larger solutes like albumin using caveolae.
Transendothelial channels - caveolae come together to form open channels that inflammatory cells can pass through.
What are caveolae?
Smooth membrane invaginations and vesicles.
What is fenestrated continuous endothelium?
Found in glomerular endothelium, vessels within endocrine and exocrine glands, and intestinal mucosa.
Allow passage of anything less than 70kDa, allows bulk flow in kidney.
Permits greater Transendothelial transport of fluids and small solutes, but not macromolecules.
What Is discontinuous endothelium?
Found in liver sinusoids and bone marrow.
Have small cells, which clear colloids and soluble waste macromolecules from circulation.
Large fenestrations so have a big diameter, which allows large molecule transport in the liver.
The basement membrane is poorly formed with gaps.
What is the activity of the discontinuous endothelium?
There is high endocytic activity in the pits - receptor mediated endocytosis.
e.g. there are receptors for low density lipoproteins which allows uptake of LDL.
What are vesiculo-vacuolar organelles?
Transports fluids and solutes across the endothelium particularly in inflammatory situations.
They form transcellular channels when they connect and fuse, and form networks of pathways.
Predominantly at post-capillary venules.
How is vasodilation caused by endothelial derived mediators?
Nitric oxide (NO)
Prostacyclin
Carbon monoxide, hydrogen disulfide, endothelium derived hyperactivating factor - channel activity changes.
How is vasoconstriction caused by endothelial derived mediators?
Endothelin-1
Thromboxane A2 (platelets)
Hydrogen peroxide, superoxide anion, free radicals produced by oxidative stress.
What are nitric oxide synthases?
There are 3 types of nitric oxide synthases, including NOS III, which make nitric oxide.
They convert L-arginine to L-citrulline, and release nitric oxide.
BH4 is a cofactor that maintains the activity of NOS.
What is nitric oxide?
Freely diffusible gas that acts as a signalling molecule.
Very short half-life, so has local activity.
Its activity in blood is limited by circulating haemoglobin.
What are the functions of nitric oxide in the vasculature?
Prevents thrombosis - by dampening platelet activation and adhesion.
Anti-inflammatory, preventions leukocyte adhesion to endothelium and migration.
Antioxidant
Inhibits smooth muscle cell proliferation and migration
Atheroprotective - against atherosclerosis.
How does stress cause dilation?
Shear stress is the main mediator of nitric oxide production.
The endothelium transduces shear stress into vasorelaxation by producing NO and increases blood flow.
The endothelial cells under flow leads to alignment in the direction of flow, which induces NOS III expression, so further increases NO production.
What is the mechanism of vascular smooth muscle relaxation?
Nitric oxide activates guanylate cyclase.
This reduces [Ca2+] and cGMP phosphodiesterase activity.
This then activates protein kinase G.
PKG then limits the activation of myosin light chain kinase, so myosin-actin cross-bridge formation stops and causes relaxation.
What are additional endothelial cell derived vasodilators?
Heme-oxygenase is activated by shear stress, and produces carbon monoxide, which reduces cGMP and causes relaxation.
Prostacyclin is produced by COX enzymes, then diffuses to the smooth muscle cells and activates acetyl cyclase, producing cAMP and vasodilation.
What is endothelial dysfunction?
In aging, there is reduced vasodilation and more pro-inflammatory and pro-thrombotic state.
This is associated with reduced bioavailability of nitric oxide.
Blood vessels may become damaged and leaky with the loss of endothelial cells.
What are the consequences of endothelial dysfunction?
It increases the risk of cardiovascular disease.
It is a prelude to the development of atherosclerotic plaques.
It is caused by diabetes and metabolic syndrome, and general aging.
How is the endothelium involved in haemostasis?
Provides a non-thrombogenic surface to maintain blood flow:
Inhibits the activation of coagulation factors.
Breaks down clots that start to form.
Inhibits platelet adhesion and activation by nitric oxide.
What are the anti-coagulant properties of endothelium?
Tissue factor pathway inhibitor - binds tissue factor to block activation of the extrinsic pathway.
Anti-thrombin III - localised on the glycocalyx, it binds and inactivates thrombin so doesn’t clot.
Thrombomodulin - activates protein C which degrades clotting factors.
Nitric oxide and prostacyclin prevent platelet adhesion.
Tissue plasminogen activator - activates plasmin for fibrinolysis.
What is the endothelial regulation of haemostasis?
Procoagulant activity when endothelial cells are damaged:
Induces tissue factor, when injured or exposed to pro-inflammatory cytokines.
Increased plasminogen activator inhibitor expression.
Von Willebrand factor is released from Weibel Palade bodies for platelet adhesion.
