CVS 17 - Atherosclerosis, role of the vascular endothelium Flashcards
What are the three 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
What is the process by which endothelial cells know that they need to form a single layer?
contact inhibition
State some roles of the endothelial cells.
Angiogenesis
Vascular tone and permeability
Thrombosis and haemostasis
Inflammation
State some stimuli of endothelial cell dysfunction (disruption of active resting state of endothelium)
The active resting state of the endothelium can be disrupted to induce a more, INFLAMMATORY, THROMBOTIC AND PROLIFERATIVE PHENOTYPE
Triggers: Turbulent flow in vessels, Inflammation, Oxidative Stress, Hypertension, Hyperglycaemia, Smoking, Pathogens, Oxidised LDL
THIS RESULTS IN ENDOTHELIAL DYSFUNCTION AND DEVELOPMENT OF AN ATHEROGENIC PHENOTYPE
What are the 5 main features of endothelial dysfunction in atherosclerosis?
- Leukocyte recruitment
- Permeability
- Blood flow
- Angiogenesis
- Senescence
Describe senescence
= growth arrest that halts the proliferation of ageing/damaged cells
Good because prevents transmission of damage to daughter cells
Bad because senescent cells are pro-inflammatory and pro-thrombotic
Senescent cell shave specific marker - b-gal
Describe the effect of disturbed blood flow on endothelial cells.
Normal blood flow is laminar
Disturbed blood flow is turbulent, it happens at branchpoints
Rate of flow exceeds critical velocity
Disturbed blood flow promotes: coagulation, leukocyte adhesion, SMC proliferation, endothelial apoptosis, loss of NO production.
VS
Laminar blood flow promotes: anti-thrombotic, anti-inflammatory factors, NO produc, inhibition of SMC proliferation.
Why is NO essential for a healthy CVS?
- reduces oxidation of LDL
- vasodilator
- reduces platelet activation
- inhibits monocyte adhesion
- reduces release of superoxide radicals
- reduces proliferation of SMC
How are epigenetics involved in atherosclerosis?
Disturbed blood flow upregulates DNA methyltransferase leading to hypermethylation of promoters of antiatherogenic genes, therefore reducing their expression so increasing atherogenesis.
Describe why leukocyte recruitment is a feature of endothelial dysfunction in atherosclerosis.
Leukocyte recruitment normally happens in post-capillary venules, not large arteries, as a normal response to inflammation.
L-selectin expressed by leukocyte - weak interaction with endothelium.
Inflammation, Oxidative Stress: E and P selectin expressed by endothelium (activation)
Chemoattractants formed due to interaction.
This leads to integrins expression
Bind to integrin receptors on endothelium
Cytoskeletal conformational changes-
Paracellular transport and transcytosis
How are the large vessels different to the post-capillary venules for leukocyte recruitment?
Beyond the endothelium there is a THICK layer which the leukocytes cannot get through so they get stuck in the sticky subendothelial space.
What triggers angiogenesis?
Hypoxia
Why is angiogenesis, in the context of cardiovascular disease, related to the Janus paradox?
Angiogenesis is bad for atherosclerosis - Angiogenesis promotes plaque growth and instability- contributes to necrotic core
Increased oxygen demand (relative hypoxia) due to insufficient oxygen diffusion in thickened tunica intima and increased O2 demand from local inflammatory response
EXTEND FROM VASA VASORUM TO TUNICA INTIMA AND PLAQUE CORE
Angiogenesis is good for myocardial infarction - therapeutic angiogenesis could reoxygenate ischaemic tissue downstream of an occlusion
How does vessel permeability contribute to the formation of atherosclerosis?
By LDL trapping
