vascular endothelium

Question 1

Where are most of endothelial cells?

Answer 1

Within the vasculature

Question 2

What are the 3 layers of the endothelium and what do they contain? Which blood vessels don’t have these 3 layers

Answer 2

(from inside to outside)

• Tunica intima (endothelial cells), tunica media (smooth muscle cells) & tunica adventitia (vasa vasorum, nerves).
• Capillaries & venules do not have these layers

Question 3

What is the structure of capillaries and venules?

Answer 3

Endothelium, supported by mural cells (pericytes) & a basement membrane

Question 4

What is the microvascular endothelium a source of ?

Answer 4

Angiocrine factors required for maintenance of tissue homeostasis & organ regeneration

Question 5

What does dysfunction of the endothelium lead to?

Answer 5

Contributes to disease more than any other organ (ischaemia, chronic inflammatory diseases, cancer, diabetes)

Question 6

Why are not all blood vessels the same? What is an example of this?

Answer 6

Tissue-specific vasculature: function in different systems is different.

• liver & kidney have very permeable vasculature because of filtration functions so look different.
• Organotypic (tissue-specific) properties & expression profiles

Question 7

What is the structure of endothelial cells?

Answer 7

• Very extensive so large surface area.
• Very flat - 1-2μm thick & 10-20μm in diameter.
• Formed by monolayer of endothelial cells (1 cell deep)

Question 8

What is contact inhibition?

Answer 8

When endothelial cell-cell junctions are established resulting in cells telling each other to stop growing

Question 9

How long do endothelial cells usually survive?

Answer 9

Long life and have low proliferation rate (unless new vessel needed - angiogenesis)

Question 10

How are endothelial cells heterogenous?

Answer 10

Functions and phenotype depend on location

Question 11

What are key functions controlled by the endothelium?

Answer 11

• Provide angiocrine signals for tissue homeostasis.

- Functions controlled by endothelium include inflammation, permeability, vascular tone, thrombosis, angiogenesis.

Question 12

What are the molecules that endothelial cells can produce and for what functions?

Answer 12

• For vascular tone permeability can produce vasoconstrictive & vasodilative factors.
• For thrombosis - anti-thrombotic and pro-thrombotic factors.
• For inflammation - anti-inflammatory & pro-inflammatory factors.
• Angiogenesis: anti-proliferative and pro-angiogenic factors

Question 13

What happens in the resting endothelium and when endothelium is activated? What happens during chronic activation of the endothelium (and by what)?

Answer 13

• In resting endothelium anti pathways switched on (anti-inflammaotry, anti-thrombotic etc).
• In activated endothelium pro-factors switched on to respond to event and these usually revert back to balance.
• Chronic activation of endothelium (eg. Atherosclerosis, smoking, viruses, inflammation) promotes thrombosis, increased permeability, leukocyte recruitment etc

Question 14

What is the pathogenesis of atheroscerlosis?

Answer 14

• initial injury due to factors activating endothelium.
• Increase in leukocyte recruitment and accumulation of leukocytes in sub-endothelial space.
• Increased permeability of lipoproteins in sub-endothelial space and subsequent phagocytosis of these form foam cells leading to advanced complicated lesion of atherosclerosis, causing more macrophages to accumulate forming necrotic core & stimulating angiogenesis from vasa vasorum in tissue

Question 15

What are stimuli for endothelial cell dysfunction in atherogenesis?

Answer 15

Hypertension (ANGII & ROS), hypercholesterolinaemia (oxidatively modified lipoprotein), diabetes, sex hormone imbalance (oestrogen deficiency, menopause), ageing, oxidative stress, pro-inflammatory cytokines IL-1 & TNF, infectious agents, environmental toxins, turbulent blood flow

Question 16

How does leukocyte recruitment happen into tissues during inflammation/infection?

Answer 16

During inflammation usually leukocytes adhere to endothelium of post-capillary venules to transmigrate into tissues

Question 17

How does leukocyte recruitment happen in atherosclerosis? where does this happen?

Answer 17

• Leukocytes roll along endothelium, spread, find junctions to get through (inflammation activates endothelium to express molecules promoting this).
• In atherosclerosis this happens in large arteries.
• Leukocytes go through endothelium but find many walls they cant pass through and get stuck in subendothelial cells.
• Monocytes migrate there, become macrophages and then foam cells

Question 18

how does vascular permeability happen in atherosclerosis and what does this lead to?

Answer 18

• Endothelium regulates fluid & molecules going in/out blood and tissues.
• Increased permeability results in leakage of plasma proteins through junctions into subendothelial cells.
• Lipoproteins find leaky junctions, get oxidised in subendothelium and macrophages engulf lipoproteins to make foam cells

Question 19

What is the shear stress principle in atheroclerosis?

Answer 19

• Atherosclerosis preferentially at bifurcations & curvatures of vascular tree because of non-uniform flow and haemodynamic forces.
• Laminar flow in straight arteries so wall shear stress high and directional.
• In curves, turbulent flow causes non-uniform and irregular distribution of wall shear stress.

Question 20

What does laminar blood flow promote? What does turbulent blood flow promote?

Answer 20

• Laminar flow promotes anti-thrombotic & anti-inflammatory factors (thrombomodulin), endothelial survival, inhibits SMC proliferation, promotes nitric oxide production.
• Turbulent flow promotes thrombosis, inflammation, endothelial apoptosis, SMC proliferation, loss of nitric oxide production

Question 21

What is nitric acid and its roles?

Answer 21

Regulator of vascular function - dilation of blood vessels, reduces platelet adhesion, inhibits monocyte adhesion, reduces SMC proliferation, reduces release of superoxide radicals, reduces oxidation of LDL cholesterol

Question 22

What is angiogenesis and how does it happen?

Answer 22

• Formation of new blood vessels sprouting from existing vessels.
• Endothelial cells hit by signalling of multiple hypoxia so endothelial cell activation, proliferation, migration and formation of new sprout

Question 23

What is angiogenesis necessary for?

Answer 23

Embryonic development, menstrual cycle, wound healing

Question 24

How can angiogenesis be bad and good in CV disease?

Answer 24

• Bad: promotes plaque growth. In advanced plaques in atherosclerosis angiogenesis stimulated in vasa vasorum because lesion is chronic inflammatory disease.
• Good: in MI occlusion of coronary artery we can induce angiogenesis downstream of blockage to re-vascularise ischaemic area and prevent loss of tissue

Question 25

What are circulating endothelial cells a sign of? What can it be corrected with?

Answer 25

-Sign of endothelial damage (shed because of damage). Corrected with anti-coagulation

Question 26

What is thrombo-inflammation and what can it cause? When does it occur?

Answer 26

Loss of normal anti-thrombotic and anti-inflammatory action of endothelial cells.
-Can cause thrombosis. Occurs in many disorders (sepsis, ischaemia-perfusion injury)

Question 27

what are the possible ways that infection of covid can cause thrombosis?

Answer 27

1. cytokine storm activates endothelium and causes endothelial damage (pro-coagulant switch)
2. sars-cov2 enters endothelial cells causing direct damage

Question 28

Does covid replicate in endothelial cells?

Answer 28

ACE2 expressed on epithelial, not endothelial cells. So no.