Vascular Endothelium Flashcards
Atherosclerosis is a …………. ……………………… ……………. of the arteries
Atherosclerosis is a chronic inflammatory disease of the arteries
Pathogenesis of Atherosclerosis: Response-to-injury Model
What are the three layers of blood vessels and what do they contain?
Blood vessels consist of THREE LAYERS (except for capillaries and venules)
Tunica Intima - ENDOTHELIUM
Tunica Media - Smooth Muscle Cells
Tunica Adventitia - Vasa Vasorum, Nerves
NOTE: The vasa vasorum is a network of small blood vessels that supply the walls of large blood vessels
What is contact inhibition?
Vascular Endothelium
There are subtle differences in different endothelia
Endothelia forms a single layer of cells in the blood vessel
When the endothelial cells divide they know that they have to form a monolayer and this is called CONTACT INHIBITION
Once formed, the endothelial cells are pretty stable, you don’t get a lot of new endothelial cells forming
You get formation of new endothelial cells if you need new blood vessels to form e.g. during healing
Endothelial cells regulate essential functions of blood vessels
The critical functions of endothelial cells involve affecting:
List 4
The critical functions of endothelial cells involve affecting:
Inflammation
Vascular Tone and Permeability
Angiogenesis
Thrombosis and Haemostasis
What is Contact Inhibition?
When the endothelial cells divide they know that they have to form a monolayer and this is called CONTACT INHIBITION
Regulation of Endothelial Homeostasis
What type of state do endothelial cells tend to maintain- healthy?
What type of state is there when you cut yourself?
How does atherosclerosis fit into this?
Regulation of Endothelial Homeostasis
In healthy tissue, the endothelial cells tend to maintain an anti-inflammatory, anti-thrombotic state
If you have some inflammation or you cut yourself, the endothelium flip to produce pro-inflammatory, pro-thrombotic, pro-angiogenic factors
The problem with atherosclerosis is that the endothelium receives a chronic number of stimuli due to the high pressure, high glucose etc. which translates to cellular signals which keeps the endothelia in an activated state thus stopping it from flipping back to the normal state
List some pathophysiological stimuli of endothelial dysfunction in Atherogenesis
Leukocyte recruitment in atherosclerosis
- Recruitment of blood leukocytes into tissues takes place normally during inflammation: leukocyte adhere to the endothelium of ……….. ………………. …………. and transmigrate into tissues
- In atherosclerosis, leukocytes adhere to activated endothelium of ……….. ………………. and get stuck in the subendothelial space
- Newly formed ……….. ………………. ……… at the base of developing lesions provide a further portal for leukocyte entry
Leukocyte recruitment in atherosclerosis
- 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
Explain the process of luekocyte recruitment?
There are molecules on the leukocyte that allow them to interact with the endothelium but they are generally switched off
Some are not switched off (e.g. selectins) but these don’t have partners on the endothelium to bind to - so they might touch the endothelium then come away
When inflammation occurs, the endothelium gets activated and it starts to express ligands for the leukocytes
You have selectins on the leukocyte which can weakly interact with the endothelium and make the leukocyte roll
Inside the leukocyte there are signals which activate the integrins (switching them to the high affinity state)
The integrins can then strongly bind to the ligands on the endothelium
The leukocyte then binds, adheres and transmigrates
MO=inflammation factor
Endothelial Junctions
Leukocytes transmigrate by squeezing through endothelial junctions
Top Photo - green is the nuclei and red is a protein called V-cadherin which is present at the junctions
At the junctions, two endothelial cells are very close to each other and the cell membrane proteins on each cell bind in a ………………… way
This binding of membrane proteins creates a ……………..
The junctions can …………….. and …………….. to allow things to go through without the whole endothelium falling apart
NOTE: there are some mutations in some of the molecules involved in this process that are not compatible with life - there are babies born with mutations in leukocyte integrins who only live for around 3 months because they are unable to deal with infection
Endothelial Junctions
Leukocytes transmigrate by squeezing through endothelial junctions
Top Photo - green is the nuclei and red is a protein called V-cadherin which is present at the junctions
At the junctions, two endothelial cells are very close to each other and the cell membrane proteins on each cell bind in a homophilic way
This binding of membrane proteins creates a zipper
The junctions can zip and unzip to allow things to go through without the whole endothelium falling apart
NOTE: there are some mutations in some of the molecules involved in this process that are not compatible with life - there are babies born with mutations in leukocyte integrins who only live for around 3 months because they are unable to deal with infection
Venules vs Arteries
This is a problem in atherosclerosis because physiologically, this transmigration process occurs in the ………….. ………….. where the ………….. goes through the ………….. ………….. , meets the basement membrane and chews the basement membrane with enzymes allowing it to pass through to the tissue
If a leukocyte adheres to the inside of a coronary artery or aorta - once it has gone through the endothelium it’s going to find a big thick layer which it CAN NOT go through and this is how atherosclerosis starts
Venules vs Arteries
This is a problem in atherosclerosis because physiologically, this transmigration process occurs in the post-capillary venules where the leukocyte goes through the endothelial junctions, meets the basement membrane and chews the basement membrane with enzymes allowing it to pass through to the tissue
If a leukocyte adheres to the inside of a coronary artery or aorta - once it has gone through the endothelium it’s going to find a big thick layer which it CAN NOT go through and this is how atherosclerosis starts
Vascular Permeability
Increased permeability results in the leakage of plasma proteins through endothelial junctions into the subendothelial space
Right below the endothelium there is a layer of sticky molecules (collagen and proteoglycan)
Lipoprotein Trapping and Oxidative Modification
Here you have lipids and the yellow crosses are the sticky proteins in the subendothelium (collagen and proteoglycans)
When the endothelium becomes activated, the cholesterol goes under the endothelial layer
The LDLs then get modified as it is a very oxidative environment
The LDLs then get stuck in the subendothelial layer
The macrophages then come and phagocytose the LDLs forming FOAM CELLS
This is the source of the chronic inflammation
Blood Flow
Atherosclerosis is not evenly distributed across the vasculature, it tends to occur at …………….. …………..
This is because you get …………….. ………….. at …………….. …………..
Name 3 things laminar blood flow promotes?
Name 4 things Turbulent flow promotes?
Blood Flow
Atherosclerosis is not evenly distributed across the vasculature, it tends to occur at BRANCH POINTS
This is because you get turbulent flow at branch points
Laminar flow can be sensed by the endothelium as a positive protective signal - this means that it triggers the production of a lot of protective molecules e.g. nitric oxide
Turbulent flow triggers the balance to go the other way and activates the inflammatory and thrombotic pathways
Laminar blood flow promotes:
Nitric oxide production
Factors that inhibit coagulation, leukocyte adhesion, smooth muscle cell proliferation
Endothelial survival
Turbulent blood flow promotes:
Coagulation, leukocyte adhesion, smooth muscle cell proliferation
Endothelial apoptosis
Name 6 protective effects of nitric oxide (not nitrous)
Endothlium exposed to laminar flow produces athero protective molecules- laminar flow activates athero protective pathways. Some of them are controlled by these transcription factors called KLF2 and KLF4.
The opposite occurs for turbulent flow and there is an upregulation of NF kappa B
What is angiogenesis?
When tissue is ………….., it will release chemicals which activates the existing blood vessels which triggers a change in the cells
The cells that becomes a tip cell takes over and controls the formation of the blood vessel
You end up with a stabilised blood vessel forming
When tissue is hypoxic, it will release chemicals which activates the existing blood vessels which triggers a change in the cells
The cells that becomes a tip cell takes over and controls the formation of the blood vessel
You end up with a stabilised blood vessel forming
Angiogenesis plays a detrimental and beneficial role in cardiovascular disease
Angiogenesis plays a detrimental and beneficial role in cardiovascular disease
On one hand, angiogenesis promotes the………………… …… ……………….. ……………………
When you have an advanced plaque and it gets to a size where there is a lot of ……………….. debris inside and there is ……………….. - the ……………….. stimulates angiogenesis from the little vessels (……………….. ………………..)
The vasa vasorum vessels are ……………. and more leukocytes will come in and contribute to the growth of the atherosclerotic plaque
What is the beneficial side of angiogenesis?
Angiogenesis and Cardiovascular Disease - The Janus Paradox
Angiogenesis plays a detrimental and beneficial role in cardiovascular disease
On one hand, angiogenesis promotes the growth of atherosclerotic plaques
When you have an advanced plaque and it gets to a size where there is a lot of necrotic debris inside and there is hypoxia - the hypoxia stimulates angiogenesis from the little vessels (vasa vasorum)
The vasa vasorum vessels are fragile and more leukocytes will come in and contribute to the growth of the atherosclerotic plaque
ON THE OTHER HAND - one of the main problems for people who suffer from acute myocardial infarction is that the tissue which suffered ischaemia will become fibrotic and hence the patient will develop heart failure
Some interventional cardiologists had the idea that if we could act really quickly after an acute myocardial infarction to reoxygenate the myocardium downstream of the occlusion in the coronary arteries using THERAPEUTIC ANGIOGENESIS, we could prevent the tissue damage and hence prevent heart failure
This is the good side of angiogenesis in cardiovascular disease
Define Senescence?
What is the bad thing about senescence?
What can induce Endothelial senescence?
As senescent cells have a ……………………… and ………………………. phenotype, they can contribute to atherosclerotic plaque progression
Senescence
Senescence applies to a lot of cells in the body
Senescence is growth arrest that halts the proliferation of ageing and/or damaged cells
This is a clever way of making sure that damaged cells don’t take over and is considered to be a protective mechanism against cancer
The bad thing about senescence is that senescent cells can develop a PROINFLAMMATORY PHENOTYPE
This is stained for senescent cells - shows that senescent cells are found in atherosclerotic lesions
Endothelial senescence can be induced by cardiovascular risk factors such as oxidative stress
As senescent cells have a pro-inflammatory and pro-thrombotic phenotype, they can contribute to atherosclerotic plaque progression
Overview of Atherosclerosis
At the beginning you have risk factors which activate the endothelium and promotes permeability, leukocyte adhesion and leukocyte migration
Leukocytes which enter the subendothelial layer begin to phagocytose LDLs and form foam cells producing fatty streaks
After a long time, this becomes a large complex plaque with angiogenesis and senescence possible playing a role
NOTE: Red wine contains RESVERATROL which has anti-inflammatory properties on the endothelium
Red wine has a hormetic action - it is beneficial at lower doses and has cytotoxic effects at higher doses
QUESTION
Q1. Which of these processes promotes early development of atherosclerotic plaque?
Senescence
Endothelial Activation
Thrombosis
Permeability
Q2. Physiologically, leukocyte transmigration occurs:
In large arteries
In post-capillary venules
In the aorta
ANSWERS:
2 and 4
2
