vascula endothelium 2 Flashcards
(33 cards)
what do endothelial cells do?
inflammation
angiogenesis
thrombosis and haemostasis
vascular tone ad permeability
endothelial cell dysfunction in atherogenesis: stimuli
hypercholesteraemia daibetes mellitus hypertension sex hormone imbalance ageing oxidative stress proinflammatory cytokines infectious agents environmental toxins haemodynamic forces
aside from large arteries and post capillary venules, what other venules can provide a further portal for leukocyte entry
newly formed post capillary venules at the base of developing lesions provide a further portal of leukocyte entry
monocytes migrate into the subendothelial space and differentiate into
macrophages
how do the endothelial junctions allow things to go through without the whole endothelium falling apart
Leukocytes transmigrate by squeezing through endothelial 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
Define capillary
Capillary: endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)
Define post capillary venule:
Post-capillary venule: structure similar to capillaries but more pericytes
Define artery
Artery: three thick layers, rich in cells and extracellular matrix
vascular endothelium function and what happens when there is increased permeability
The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space
what happens in lipoprotein trapping and oxidative modification
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
why does atherosclerosis occur at branch points?
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
what happens in laminar flow?
Streamlined, outermost layer moving slowest and centre moving fastest
what happens in turbulent flow?
Irregular flow
Speed of fluid is continuously undergoing changes in both magnitude and direction
protective effects of laminar flow
Laminar blood flow promotes antithrombotic factors, anti-inflammatory factors, nitric oxide production, inhibition of SMC proliferation
detrimental effects of turbulent flow
Disturbed blood flow promotes coagulation, leukocyte adhesion,
SMC proliferation,
endothelial apoptosis reduced nitric oxide production
give examples of protective effects of nitric oxide on vascular endothelium
reduces oxidation of LDL cholesterol dilates blood vessels reduces platelet activation inhibits monocyte adhesion reduces proliferation of SMC in the vessel wall reduces release of superoxide radicals
blood flow patterns determine susceptibility to atherosclerosis
Early lesions of atherosclerosis in the human carotid artery develop in the area of a major curvature (carotid sinus) exposed to low time-average shear stress, a high oscillatory shear index, and steep temporal and spatial gradients. Endothelial cells at this site display an atheroprone phenotype, which promotes a proinflammatory milieu driven by the priming of the NF-κB signaling pathway, which is then perpetuated in response to subendothelial apoB LPs. NF-κB activation promotes the entry of blood-borne monocytes (blue cells) through the junctions of endothelial cells (orange cells) into the intima, and there, monocytes differentiate into macrophages (red cells). In contrast, arterial geometries that are exposed to uniform laminar flow evoke an atheroprotective endothelial cell phenotype driven by the transcriptional integrators KLF2 and KLF4. This atheroprotective endothelial phenotype, together with a decrease in LP retention, promotes an antiinflammatory and antithrombotic environment that affords relative protection from atherosclerotic lesion development.
define epigeneticcs
EPIGENETICS: functionally relevant, inheritable changes to the genomethat do not involve a change in thenucleotide sequence, which affect gene expression
3 epigenetics mechanisms
DNA methylation
Histones modifications
miRNA
blood flow regulates endothelial epigenetic pathways - STABLE FLOW
A: Stable flow (s-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.
blood flow regulates endothelial epigenetic pathways - DISTURBED FLOW
B: Disturbed flow (d-flow) upregulates DNMT expression, leading to hypermethylation of the promoter of antiatherogenic genes, such as Klf4 and HoxA5, repressing their expression.
define angiogenesis
Angiogenesis is the sprouting of new vessels from the endothelial lining of preexisting vessels.
what is angiogenesis essential for
embryonic development
menstrual cycle
wound healing
how does angiogenesis take place
Angiogenesis is totally controlled by endothelial cells and has a role in atherosclerosis
This process is more relevant to disease - e.g. it is crucial in cancer
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
