vascular endothelium Flashcards
basic structure of blood vessel → layers?
tunica adventitia with vasa vasorum, nerves
tunica media with smooth muscle cells
tunica intima with endothelium
which vessels are the exception to this structure?
capillaries and venules
what are capillaries and venules made from
endothelium supported by mural cells (pericytes) and basement membrane
nearly all cells are in contact with microvascular endothelial cells
what kind of layer do these form? (endothelial cells lining the vascular system)
acts as a barrier separating blood from tissues
cells are very flat about 1-2 micrometres thick and 10-20 micrometre diameter
thin monolayer one cell deep for contact inhibition
Large SA>1000m2 weight >100g
lifespan of endothelial cells?
long, low proliferation rate unless new vessels are needed
new vessels = angiogenesis
what do the endothelial cells control?
vascular tone, angiogenesis, haemostasis and thrombosis, inflammation, permeability, tissue homeostasis and regen
are the endothelial layers the same throughout the body?
no as there are structural functional and molecular differences
endothelial cells and microvasculature have organotypic (tissue specific) properties and gene/protein expression profiles
how do endothelial cells maintain tissue homeostasis and regeneration?
producing angiocrine factors
how does this link to each specific tissue?
angiocrine profile is tissue specific
tissue specific microenvironment influences phenotype of endothelial cells
endothelial cells are the must abundant cell type in the heart and crosstalk with cardiomyocytes
when is angiogenesis usually required?
menstrual cycle, wound healing, development
pathological causes of angiogenesis?
cancer, atherosclerosis, retinopathies, chronic inflammatory disease, ischemic disease, vascular malformations etc
what is the angiogenic switch?
tumour grows large enough to require new vessels → starts secreting angiogenic factors stimulating new vessel formation in adjacent endothelial cells (angiogenic switch)-> tumour vasculature facilitates growth and metastasis
main type of bleeding in von willebrand disease?
mucosal
when is replacement of deficient/dysfunctional clotting factors insufficient?
some patients = GI tract bleeding due to vascular malformations in the gut blood vessels
replacement therapy eg VWF and DDAVP is given in most mild cases
functions of VWF?
platelet adhesion to endothelium, stabilises factor VIII
controls angiogenesis and blood vessel integrity by regulating growth factor signalling (VEGFR2 ,Ang-2)
what characteristics of an activated endothelium can lead to atherosclerosis?
Thrombosis
Senescence
Permeability
Leukocytes recruitment
where do leukocytes migrate from blood into tissues?
mostly in post capillary venules and then transmigrate into tissues
this takes place during inflammation
Post capillary venules have a similar structure to capillaries but more pericytes
how does leukocyte migration occur
cytokine and chemokine signal → leukocyte undergoes capture, rolling, adhesion and paracellular/transcellular migration
how does this contribute to atherosclerosis pathophysiology?
leukocytes adhere to activated endothelium of large arteries → stuck into subendothelial space
monocytes in subendothelial space differentiate → macrophages → foam cells
how does vascular permeability contribute?
activated endothelium = more leaky
LDLs allowed to enter subendothelial space → oxidised and promote endothelial activation etc
Endothelial activation causes increased permeability and leakage of plasma proteins into the subendothelial space. LDL Exeter the subendothelal space get oxidized ldl and further promote endothelial activation etc. monocytes migrated into the intima space differentiate into macrophages and take up oxidized LDL making foam cells
why does atherosclerosis occur at branch points?
non-laminar flow creates non-uniform stress with disturbed flow and irregular distribution of low wall shear stress (branches)
when flow is laminar wall shear stress is high and directional (straight vessels)
whats the consequence of disturbed flow
loss of nitric oxide NO production
Promotes
Thrombosis and inflammation (leukocyte adhesion)
Endothelial apoptosis
SMC Proliferation
Loss of nitric oxide production
how does angiogenesis relate to atherosclerosis?
angiogenesis contributes to plaque formation
therapeutic angiogenesis can prevent damage after ischaemia
in what other illness does endothelial health play an important role?
SARS-CoV-2
Causes cytokine storm which causes endothelial activation thus procoagulant switch
how to measure endothelial cell heterogenity
single cell RNAseq to examine the transcriptional signature of individual cells
cells are dissociated and then isolated. RNA extracted and single cell sequecning occurs where you can see the expression profile after. Seurat clustering where each dot is a cell and cells are grouped according to similarity of gene expression
what drugs are used for solid tumours
anti-angiogenic drugs with chemotherapy
response to injury model
Pathogenesis of atherosclerosis
endothelial dysfunction
1.increased permeability in the endothelium to lipoproteins occur via NO,prostacyclin,PDGF,angiotensin II
2.leukocytes adhesion molecules are upregulated such as p selectin and integrins
3.leukocytes migrate into the intima of the artery
fatty streak formation
4.monocytes differentiate into macrophages and engulf oxLDL forming foam cells and thus fatty streak
advanced complicated lesions
5.as fatty streak progresses to advancing stages it forms a fibrous cap which falls of the lesion thus represents healing or fibrous response to injury
6.fibrous cap contains leukocytes lipids and debris forming a necrotic core
laminar blood flow promotes
anti thrombotic anti inflammatory factors
endothelial survival
inhibition of SMC proliferation
NO production
Angiogenesis and cardio disease
Angiogenesis also promotes plaque growth (janus paradox)
Therapeutic angiogenesis prevents damage post ischaemia
NO effects
Reduces oxidation of LDL cholesterol
Reduces release of superoxide radicals
Reduces proliferation of SMC jn vessel wall
Inhibits monocytes adhesion
Reduces platelet activation
Size of capillaries
5-10 micrometers
What activates the endothelium
Inflammation
High bp
OxLDL
High glucose
Virus
Smoking
Mechanical stress
