9. Vascular endothelium 2 Flashcards
What are the 3 layers of blood vessel walls and what is contained in each layer?
Tunica intima: endothelial cells
Tunica media: smooth muscle cells
Tunica adventitia: vasa vasorum and nerves
Vaso vasorum
small blood vessels that supply the walls of large blood vessels
List 4 critical functions endothelial cells are involved in
Inflammation
Vascular Tone and Permeability
Angiogenesis
Thrombosis and Haemostasis
A common way endothelial cells controls processes
Control many processes by keeping a balance between pro and anti
Various stimuli can chronically activate the endothelium
After many years of this stimuli, the balance becomes tilted permanently on the activated side
This promotes atherosclerosis
10 agents that can chronically activate the endothelium
Hypertension Hypercholesterolemia Diabetes mellitus Sex hormone imbalance Ageing Oxidative stress Proinflammatory cytokines Infections agents Environmental toxins e.g. cigarette smoke Haemodynamic forces e.g. disturbed blood flow
When and where does leukocyte recruitment normally take place? Why does this normal recruitment of leukocytes not cause atherosclerosis?
During inflammation
Post-capillary venules
Normally, the leukocytes transmigrate into tissues
What happens to leukocytes when they adhere to activated endothelium of large arteries?
They get stuck in the subendothelial space
Newly formed post-capillary venules at the base of developing lesions provide a further portal for leukocyte entry
Monocytes migrate into the subendothelial space differentiate into macrophages
How are the large vessels different to the post-capillary venules?
Beyond the endothelium there is a THICK layer which the leukocytes cannot get through
So they get stuck in the sticky subendothelial space and accumulate there
Briefly describe leukocyte recruitment.
Leukocytes have weak interactions via selectins.
When the endothelium is activated, it will express chemokines that bind to receptors on the leukocytes and switches their integrins to the high affinity state and subsequent binding to its ligand on the endothelial cells. This allows leukocyte immobilisation on the endothelial surface and transmigration.
What activates the endothelium?
An inflammatory trigger
Describe the development and life of endothelial cells
Endothelial cells grow next to each other (not 3D) because of contact inhibition (when 2 growing cells touch, they engage with molecular pathways that “say” stop proliferating)
Endothelial cells don’t divide much and have a long life.
There are junctions between endothelial cells (which leukocytes can squeeze through)
Describe the structure of a capillary
endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)
The BM is thin so leukocytes can get through.
How does a post-capillary venue differ to a capillary?
Structure similar to capillaries but more pericytes
What does Increased endothelial permeability result in?
Leakage of plasma proteins through the junctions into the subendothelial space.
Can lead to swelling (Oedema)
What happens to lipoproteins that pass through the activated endothelium?
Lipoproteins bind to proteoglycans and get oxidised
Macrophages that have passed through “gobble up” lipoproteins: this forms foam cells and “fatty streaks”
Where do Atherosclerotic plaques form preferentially and why?
At branch points
In a bend/narrowing flow becomes turbulent
Endothelial cells sense flow and their transcription factors are activated by type of flow
List 4 protective effects of LAMINAR FLOW
Promotion of: Antithrombotic factors Anti-inflammatory factors NO production Inhibition of SMC proliferation
List 5 negative effects of TURBULENT FLOW
Promotion of: Coagulation Leukocyte adhesion SMC proliferation Endothelial apoptosis Reduced NO production
6 protective effects of nitric oxide (NO)
Dilates blood vessels
Reduces platelet activation
Inhibits monocyte adhesion
Reduces proliferation of SMC in the vessel wall
Reduces release of superoxide radicals
Reduces oxidation of LDL cholesterol (major component of plaque)
Which endothelial transcription factors are activated in laminar and turbulent flow?
Laminar: KLF2 and KLF4; anti-inflammatory, anti-thrombotic
Turbulent: NF-KB; pro-inflammatory, pro-thrombotic
3 key epigenetic mechanisms
DNA methylation
Histones modifications
miRNA
Blood flow regulates endothelial epigenetic pathways, mechanoreceptors sense blood flow, resulting in changes in chromatin
Stable flow: downregulates expression of DNA methyltransferases (DNMTs), which allows the promoter of antiatherogenic genes, e.g. Klf4 and HoxA5, to remain demethylated, enabling their expression.
Disturbed flow (d-flow) upregulates DNMT expression, leading to hypermethylation of the promoter of antiatherogenic genes, e.g. Klf4 and HoxA5, repressing their expression.
Angiogenesis
The formation of new blood vessels by sprouting from pre-existing vessels.
What 3 processes is angiogenesis essential for?
Embryonic development
Menstrual cycle
Wound healing
What environmental factor can cause angiogenesis?
Hypoxia induces production of growth factors causing growth of new blood vessels
Why is angiogenesis, in the context of cardiovascular disease, related to the Janus paradox?
BAD for atherosclerosis: an advanced plaque has a lot of necrotic debris inside and there is hypoxia: stimulates angiogenesis from vasa vasorum (fragile): more leukocytes enter and contribute to the growth of the plaque
GOOD for myocardial infarction: therapeutic angiogenesis could reoxygenate ischaemic tissue downstream of an occlusion, preventing tissue damage and heart failure
What is cell senescence?
Growth arrest that halts the proliferation of ageing and/or damaged cells
Senescent cells have distinctive morphology and acquire specific markers (e.g. b-gal)
Benefits of cell senescence
Protective against cancer because it prevents damaged cells from proliferating
Replicative senescence
the limited proliferative capacity of human cells in culture
What is the problem with cell senescence?
Senescent cells are pro-inflammatory and contribute to may diseases
Atherosclerosis and endothelial senescence
Senescent endothelial cells are found in atherosclerotic lesions (induced by cardiovascular risk factors (e.g. oxidative stress))
Senescent cells have a proinflammatory and prothrombotic phenotype, therefore may contribute to atherosclerosis plaque progression and its complications
What cardiovascular benefits are given by resveratrol in red wine?
Prevents pro-inflammatory changes induced by a high fat meal in leukocytes
Improves endothelial function in Obese T2DM
Hormetic action of resveratrol
beneficial effects at lower doses
cytotoxic effects at higher doses
List 3 factors that can promote vascular health
Diet
Exercise
Statins
Describe the formation of an atherosclerotic plaque
Chronic stimulation of large vessels causes endothelial activation
Permeability increases
Leukocytes attach and migrate through
Lipids also pass through, bind to proteoglycans, get oxidised and accumulate
Macrophages engulf lipids forming foam cells and fatty streaks
Formation of a necrotic core
Over time a complex atherosclerotic plaque forms
