5.12 - Vascular endothelium Flashcards
What are blood vessels lined by?
Endothelial cells
What happens when the endothelium is dysfunctional?
When dysfunctional, the endothelium contributes to more diseases than any other organ
Describe the basic structure of blood vessels (except for capillaries and venules).
- tunica adventitia - vasa vasorum, nerves
- tunica media - smooth muscle cells
- tunica intima - endothelium
What is the structure of capillaries and venules?
Formed by endothelium, supported by mural cells (pericytes) and a basement membrane
What are capillaries the site of?
Site of exchange of nutrients and oxygen between blood and tissue
What are nearly all cells in the body in contact with?
Microvascular endothelial cells
What percentage of endothelial cells reside in the microvasculature?
98%
What are some features of endothelial cells lining the vascular system? (4)
- the endothelium acts as a vital barrier separating blood from tissues
- very extensive - SA>1000m2, weight>100g
- endothelial cells are very flat, about 1-2um thick and 10-20um in diameter
- endothelial cells form a monolayer, one cell deep (contact inhibition)
What is contact inhibition?
- when two cells come together to form a junction and stop each other from growing
- allows the endothelial cells to form a flat monolayer
What is the lifespan and proliferation rate of endothelial cells?
In vivo, it is thought that endothelial cells live a long life and have a low proliferation rate, unless new vessels are required (angiogenesis)
What do endothelial cells regulate? (6)
Essential functions of blood vessels and tissues:
- permeability
- inflammation
- haemostasis & thrombosis
- angiogenesis
- vascular tone
- tissue homeostasis and regeneration
What do endothelial cells secrete to regulate the vascular homeostatic balance for haemostasis & thrombosis?
- procoagulant factors:
- VWF
- thromboxane A2
- thromboplastin
- factor V
- platelet activating factor
- plasminogen activator inhibitor
- antithrombotic factors:
- prostacyclin
- thrombomodulin
- antithrombin
- plasminogen activator
- heparin
What do endothelial cells secrete to regulate the vascular homeostatic balance for angiogenesis?
- growth factors (insulin like GF, transforming GF, colony stimulating factor)
- matrix products (fibronectin, laminin, collagen, proteoglycans, proteases)
What do endothelial cells secrete to regulate the vascular homeostatic balance for vascular tone/permeability?
- vasoconstricting factors (ACE, thromboxane A2, leukotrienes, free radicals, endothelin)
- vasodilator factors (nitric oxide, prostacyclin)
What do endothelial cells secrete to regulate the vascular homeostatic balance for inflammation?
- inflammatory mediators (IL1/6/8, leukotrienes, MHC II)
- adhesion molecules (ICAMs, VCAM, selectins)
What properties do endothelial cells have that differ between tissues?
Endothelial cells and microvasculature have organotypic (tissue-specific) properties and gene/protein expression profiles (heterogenous)
What is used to examine transcriptional signature of individual endothelial cells?
- single cell RNAseq
- Seurat clustering - each dot is a cell, cells are grouped according to similarity of gene expression
Tissue –> dissociation of cells –> isolation of cells –> single cell –> RNA extraction –> cDNA synthesis –> single-cell sequencing –> expression profile –> cell type identification (Seurat Clustering)
What is the Human Cell Atlas?
An international collaborative consortium that charts the cell types in the healthy body, across time from development to adulthood
How do endothelial cells directly control tissue-specific cell functions?
- endothelial cells produce angiocrine factors which are essential for the maintenance of tissue homeostasis and regeneration
- the angiocrine profile of each tissue-specific microvascular endothelium is different
- conversely the tissue-specific microenvironment influences the phenotype of endothelial cells
What cell type is the most abundant cell type in the heart?
Endothelial cells are the most abundant cell type in the heart and crosstalk with cardiomyocytes
What is the process of sprouting angiogenesis?
- hypoxia (driver)
- angiogenic factor production (VEGFs from non-endothelial cells)
- factors are released and bind to endothelial cell receptors on the capillary
- endothelial cells activated
- endothelial cells proliferate
- directional migration
- ECM remodelling
- tube formation
- loop formation
- vascular stabilisation
What are some physiological causes of angiogenesis? (3)
- development
- menstrual cycle
- wound healing
What are some pathologic causes of angiogenesis? (6)
- cancer
- retinopathies
- atherosclerosis
- chronic inflammatory diseases
- ischaemic diseases
- vascular malformations
What is the angiogenic switch in cancer growth?
- small tumours receive oxygen and nutrients by diffusion from host vasculature
- larger tumours require new vessels - tumour cells secrete angiogenic factors that stimulate neovessel formation by endothelial cells in adjacent tissues (angiogenic switch)
- tumour vasculature facilitates growth and metastasis
What kind of drug can be given in clinic for a number of solid tumours?
Anti-angiogenic drugs in clinic, in combination with chemotherapy, for a number of solid tumours
What does insufficient haemostasis cause?
Bleeding
What does excessive and/or spontaneous clot formation cause?
Thrombosis
What is haemostasis?
Normal blood clotting in response to an injury
What is Von Willebrand disease?
- most common hereditary bleeding disorder due to decrease or dysfunction of von Willebrand Factor (VWF)
- characterised mainly by mucosal bleeding
- most forms are mild
How can VWD be treated in most cases?
Replacement therapy (VWF, DDAVP) effective in most cases
When is replacement therapy with VWF not sufficient in VWD?
- some patients have severe and intractable bleeding from the GI tract due to vascular malformations in the gut blood vessels
- treatment with products that replace VWF in the blood is not sufficient to control this bleeding
What is the role of VWF in haemostasis? (2)
- VWF mediates platelet adhesion to the subendothelium and platelet aggregation
- VWF stabilises circulating coagulation factor VIII
What is the role of VWF in angiogenesis?
- endothelial VWF controls blood vessel formation (angiogenesis) and integrity, partly by regulating growth factor signalling (VEGFR2; Ang-2)
- VWF-deficient endothelial cells show increased angiogenesis
How do you control GI bleeding in VWD?
Target blood and blood vessels (circulating VWF, endothelial angiogenic pathways)
What pathways are on when the endothelium is resting? (3)
- anti-inflammatory
- anti-thrombotic
- anti-proliferative
What pathways are switched on when the endothelium is activated? (3)
- pro-inflammatory
- pro-thrombotic
- pro-angiogenic
What factors can trigger chronic activation of the endothelium? (7)
- smoking
- viruses
- mechanical stress
- inflammation
- high blood pressure
- OxLDL
- high glucose
What does chronic activation of the endothelium cause? (4)
- thrombosis
- senescence (ageing of endothelial cells)
- leukocyte recruitment
- permeability
–> atherosclerosis
What can a chronically activated endothelium lead to?
Atherosclerosis
Describe the response to injury model of the pathogenesis of atherosclerosis?
- initial injury results in activation of endothelium
- this increases endothelial permeability, upregulation of systems that promote leukocyte migration and adhesion
- leukocytes move into and accumulate in subendothelial space
- they phagocytose the lipids in this space to create foam cells
- this process slowly evolves into an advanced, complicated lesion of atherosclerosis
- macrophages accumulate –> formation of a necrotic core and angiogenesis is promoted
Describe the response to injury model of atherosclerosis in three main steps.
- endothelial dysfunction in atherosclerosis
- fatty-streak formation in atherosclerosis
- formation of an advanced, complicated lesion of atherosclerosis
What are the four mechanisms of endothelial dysfunction in the pathogenesis of atherosclerosis?
- leukocyte recruitment
- permeability
- shear stress
- angiogenesis
What is leukocyte recruitment?
When inflammatory agents activate endothelium to express molecules that cause leukocytes to be captured, adhere, roll along endothelium then migrate through cell junctions to reach site of inflammation
Where does recruitment of leukocytes into tissues normally occur?
- during inflammation - leukocytes adhere to endothelium of post-capillary venules and transmigrate into tissues
- the structure of post-capillary venules is similar to capillaries but more pericytes
Where does leukocyte recruitment occur in atherosclerosis?
- leukocytes adhere to activated endothelium of large arteries and get stuck in the subendothelial space
- monocytes migrate into the subendothelial space, differentiate into macrophages and become foam cells
What does the endothelium regulate and how does endothelial activation affect this?
- endothelium regulates permeability - flux of fluids and molecules from blood to tissues and vice versa
- endothelial activation causes increased permeability and leakage of plasma proteins into the subendothelial space
What do lipoproteins do when there is increased vascular permeability?
- lipoproteins (LDL) enter the subendothelial space, get oxidised (OxLDL) and further promote endothelial activation
- monocytes migrated into the intima space differentiate into macrophages and take up oxidated LDL (via scavenger receptors) –> foam cells
At what parts of the vascular system are atherosclerotic plaques more likely to occur?
- at branch points - bifurcations and curvatures of the vascular tree
- the flow patterns and haemodynamic forces are not uniform in the vascular system
How does blood flow differ between straight parts and in branches/curvatures of the vasculature?
- in straight parts of the arterial tree, blood flow is laminar and wall shear stress is high and directional
- in branches and curvatures, blood flow is disturbed with non-uniform and irregular distribution of low wall shear stress
What does laminar blood flow promote? (4)
- anti-thrombotic, anti-inflammatory factors
- endothelial survival
- inhibition of SMC (vascular smooth muscle cell) proliferation
- nitric oxide production
What does disturbed blood flow promote? (4)
- thrombosis, inflammation (leukocyte adhesion)
- endothelial apoptosis
- SMC proliferation
- loss of nitric oxide production
What are the effects of nitric oxide on the cardiovascular system? (6)
- dilates blood vessels
- reduces platelet activation
- inhibits monocyte adhesion
- reduces proliferation of SMC in vessel wall
- reduces release of superoxide radicals
- reduces oxidation of LDL (major component of plaque)
What is (sprouting) angiogenesis?
The formation of new vessels sprouting from existing vessels, usually triggered by hypoxia which activates the endothelial cells
What is the JANUS paradox of angiogenesis in cardiovascular disease?
- angiogenesis promotes plaque growth
- however, therapeutic angiogenesis prevents damage post-ischaemia e.g. in MI
Key points summary - role of endothelium in atherosclerosis development?
- leukocyte recruitment - endothelial activation in large arteries causes leukocyte migration into subendothelial space, where they accumulate and contribute to plaque development
- permeability - increased permeability to lipids contributes to early plaque formation
- blood flow + shear stress - turbulent blood flow at branch points causes chronic endothelial activation –> atherosclerosis commonly at branch points
- angiogenesis - pathological angiogenesis is associated with advanced atherosclerotic plaques
How does the SARS-CoV2 infection cause severe disease through the vasculature?
- the infection causes a cytokine storm which activates endothelium and causes a procoagulant switch
- endothelium loses anticoagulant properties to prevent thrombus formation
How does COVID-19 cause endothelial disease? (5)
- bleeding/thrombosis
- inflammation
- permeability/barrier
- vascular tone
- redox balance
