18 Vascular Endothelium and Inflammation Flashcards
Q: What model describes the pathogenesis of atherosclerosis? 3 steps.
A: Response-to-injury Model
- Endothelial Dysfunction (leukocyte migration)
- Fatty-Streak Formation (foam cell formation)
- Formation of an Advanced, Complicated Lesion of Atherosclerosis (necrotic core)
Q: What’s the structure of blood vessels? (3-3,1,2)
A: Three layers (except for capillaries and venules):
Tunica intima
– Endothelium, basement membrane, (lamina propia= SM and connective T)
Tunica media
– Smooth muscle cells
Tunica adventitia
– vasa vasorum (network of small blood vessels that supply the walls of large blood vessels), nerves
Q: What is the endothelium? formed by? (3) Role? (2)
A: The Endothelium is the surface separating blood from other tissues
- monolayer of endothelial cells, one cell deep (contact inhibition allows it to be 1 layer)
- Endothelial cells are very flat, about 1-2 µm thick and 10-20 µm in diameter
- Not all endothelial cells are the same (heterogeneity)
maintain health of blood vessels
regulate essential functions of blood vessels
Q: Life of endothelial cell?
A: long life and have a low proliferation rate (unless new
vessels are required: angiogenesis)
Q: What 2 types of molecules do endothelial cells produce to aid inflammation? 3 examples each.
A: Adhesion molecules
ICAMs
VCAM
Selectins
inflammatory mediators
IL-1,6,8
leukotrienes
MHC II
Q: What 2 types of molecules do endothelial cells produce to aid vascular tone/permeability? Examples?
A: vasodilator factors
NO
prostacyclin
vasoconstricting factors ACE thromboxane II leukotrienes free radicals endothelin
Q: What 2 types of molecules do endothelial cells produce to aid haemostasis/thrombosis?
A: antithrombotic factors
procoagulant
Q: Regulation of endothelium homeostasis. What’s resting endothelium producing? (6) what can happen? usually? What is different with atherscelorisis?
A: Anti-inflammatory
Anti-thrombotic
Anti-proliferative
Pro-inflammatory
Pro-thrombotic
Pro-angiogenic
(less of these 3)
can flip over and produce less of first 3 if needed
-transient and local to area where it is needed
endothelium is activated chronically for long time-> eventually gets flipped permanently
Q: What can act as a stimulus to activate endothelium? (7) Result of an activated endothelium? (4)
A: Mechanical stress Viruses Smoking High blood pressure OxLDL High glucose Inflammation
Thrombosis Permeability
Senescence
Leukocyte recruitment
ATHEROSCLEROSIS
Q: Endothelial dysfunction in atherosclerosis. 1. leukocyte recruitment.
When does it normally occur and what first happens to them? What happens in atherosclerosis? what aids recruitment?
A: during inflammation: leukocyte adhere to the endothelium of post-CAPILLARY venules and transmigrate into tissues
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
Q: Describe the process of basic leukocyte recruitment and transmigration. (7)
A: 1. leukocytes possess receptors that have potential of binding to endothelium
- activation of endothelium -> express needed receptors
- binding occurs- first is weak via L selectin from leukocyte (to E/P selectin on endothelium)
- rolling occurs
- leukocyte becomes activated
- activation gives ability for strong binding to endothelium (integrin from leuk and ICAM1, VCAM1 of endothelium)
- transmigration
Q: Describe endothelium junctions. What do they allow?
A: many molecules expressed that hold together = bind in homophilic way
movement through between cells without interfering with integrity of monolayer
Q: Is the process of leukocyte recruitment essential? Where can leukocyte recruitment occur? (3) Describe.
A: essential for life but in atherosclerosis = damaging
physiologically it occurs in capillaries and post capillary venules and in ather. occurs in arteries
- Capillary: endothelial cells surrounded by basement membrane and pericapillary cells (perycites)
- Post-capillary venule: structure similar to capillaries but more pericytes (contractile cells)
- Artery: three thick layers, rich in cells and extracellular matrix (leuk once recruited= trapped in subendothelial space)
Q: What’s the role of endothelium in atherosclerosis? (3)
A: Thrombosis Permeability
Senescence
Leukocyte recruitment
Q: Endothelial dysfunction in atherosclerosis. 2. permeability.
What lies behind the monolayer of endothelial cells in arteries?
How does endothelium activation affect permeability? Describe the process following this change.
A: intima= collagen and proteoglycans
Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space = trapped
- increased perm-> LDL enter
- lipoprotein oxidation
- macrophage uptake
- foam cell production
- chronic inflammation
Q: Endothelial dysfunction in atherosclerosis. 3. blood flow.
How does blood flow affect endothelial function in terms of atherosclerosis? WHY? (2)
A: 1. atherosclerosis does not occur uniformly
2. tends to occur at branch points as blood flow here is turbulent
- endothelium exposed to laminar flow produces athero-protective molecules= activate athero-protective pathways (antithrombotic and anti inflammatory) eg KLF2, 4
- endothelium phenotype exposed to turbulent flow becomes athero prone-> certain pathways (thrombotic and inflammatory) are activated= create an atherosclerosis susceptible region
Q: Compare laminar flow and disturbed flow. (2,2) When do you get turbulent flow?
A: Laminar flow
– Streamlined
– Outermost layer moving slowest and centre moving fastest
Disturbed flow (turbulent)
– Interrupted
– Rate of flow exceeds critical velocity
Fluid passes a constriction, sharp turn, rough surface
Q: What does laminar flow promote? (4) Disturbed, turbulent flow? (3)
A: Laminar blood flow promotes:
- anti-thrombotic, anti-inflammatory factors
- endothelial survival
- Nitric oxide (NO) production** important
- Inhibition of SMC proliferation
Disturbed blood flow promotes:
- coagulation, leukocyte adhesion, SMC proliferation
- endothelial apoptosis
- Loss of Nitric oxide (NO) production**
Q: What is epigenetics? 3 key mechanisms? Relevance? What can regulate epigenetics?
A: functionally relevant, inheritable changes to the genome that do not involve a change in the nucleotide sequence, which affect gene expression
- DNA methylation
- Histones modifications
- miRNA
said pathways can be targets for drugs
flow (in endo cells)
Q: How does blood flow control epigenetics in endothelial cells?
A: laminar flow downregulates expression of DNA
methyltransferases (DNMTs), which allows the promoter
of antiatherogenic genes, such as Klf4 and HoxA5, to
remain demethylated, enabling their expression.
Disturbed flow upregulates DNMT expression,
leading to hypermethylation of the promoter of
antiatherogenicgenes, such as Klf4 and HoxA5,
repressing their expression
when expression of them is repressed you get pro atherogenesis
- apoptosis EC
- proliferation SMC
- inflammation
- thrombosis
Q: Endothelial dysfunction in atherosclerosis. 4. angiogenesis.
What is angiogenesis? Triggered by?
A: Formation of new blood vessels by sprouting from
pre-existing vessels = cascade of events triggered by need for blood/oxygen = HYPOXIA TRIGGERS
Q: What’s the role of angiogenesis in CVD?
A: JANUS PARADOX
can be detrimental to atherosclerosis and CVD but also beneficial
Q: How can angiogenesis be detrimental in CVD? (3)
A: -when you have a large plaque-> leads to hypoxic environment-> produces pro atherogenic
- get angiogenesis
- this then aids plaque growth-> as the new blood vessels are exposed to the same stimuli that allowed plaque formation = can contribute to growth of plaque
Q: How can angiogenesis be beneficial in CVD? Give an example and describe.
A: -therapeutic angiogenesis prevents damage post ischaemia
- eg acute occlusion of coronary = acute interuption of blood flow = downstream tissue is deprived of oxygen = dies (infarction) = tisssue is fibrotic and unable to function as a pump -> could get heart failure
-solution given: was to deliver growth factors/stem cells to the ischemic heart region to induce new vessel
growth (fast enough to prevent death of tissue)
Q: Endothelial dysfunction in atherosclerosis. 5. senescence.
What is cellular senescence? Describe senescent cells. Specific marker?
A: growth arrest that halts the proliferation of ageing and/or damaged cell - have distinctive morphology and acquire specific markers, e.g. b-gal
Q: Why is senescence good? (2) Bad?
A: Good: prevents the transmission of damage to daughter cells (prevents damaged cell growth)
– Replicative senescence: the limited proliferative capacity of human cells in culture
– Senescence as response to stress and damage
Not so good: senescent cells are pro-inflammatory and contribute to many diseases
Q: What can induce endothelial cell senescence? Where are senescent endothelial cells found? What’s their phenotype and what can they contribute to?
A: CV risk factors, such as oxidative stress
atherosclerotic lesions
pro-inflammatory and prothrombotic phenotype and therefore may contribute to atherosclerosis plaque progression and its complications
Q: What’s the fate for a atherogenic plaque? (2)
A: rupture or be stabilised by fibrous cap
Q: How to protect the endothelium and prevent atherosclerosis?
A: promoting protective pathways (Anti-inflammatory, Anti-thrombotic, Anti-proliferative) or inhibiting inflammatory ones (Pro-inflammatory, Pro-thrombotic, Pro-angiogenic)
difficult to inhibit ^
