🫀🫁Cardio & Resp🫀🫁 - Vascular Endothelium Flashcards
What is the vascular system?
What is the structure of the blood vessel wall?
Tunica adventitia
Tunica media
Tunica intima
What is contained in the tunica adventitia?
Vasa nervosum - endothelial cells blood supply
Nerves
What is contained in the tunica media?
External elastic membrane
Smooth muscle cells
What is contained in the tunica intima?
Internal elastic membrane
Lamina propria (smooth muscle and connective tissue)
Basement membrane
Endothelium
Which are the only vessels that don’t exhibit the three layer structure?
Capillaries and venules
What are capillaries?
Capillaries and venules are formed by endothelium, supported by mural cells (pericytes) and a basement membrane
Capillaries is where the exchanges of nutrients and oxygen between blood and tissues occur
Capillaries and venules form the microvasculature
What is the role of the endothelium in the vascular system?
The Endothelium acts as a vital barrier separating blood from tissues
Very extensive: surface area > 1000 m2
Endothelial cells are very flat, about 1-2 µm thick and 10-20 µm in diameter
Endothelial cells form a monolayer, one cell deep (contact inhibition)
What is contact inhibition?
Endothelial cells stop dividing and proliferating when they come into contact with each other
Prevents excessive growth and proliferation - maintains integrity and smoothness
Regulation is crucial for maintaining vascular health - prevent atherosclerosis and abnormal clotting
What happens to endothelial cells when there is damage to the vessel wall (re contact inhibition)?
Damage leads to lifting of inhibition (as cells no longer touching) - divide and migrate to cover the wound
Repair = cells in contact again - contact inhibition is re-established
What is the lifespan of endothelial cells?
Long life - low proliferation rate
UNLESS
New vessels required - angiogenesis
How do the properties of blood vessels vary in different areas of the body?
Not all endothelial cells in the body are the same: structural, functional, and molecular differences
Endothelial cells and microvasculature have organotypic (tissue-specific) properties and gene/protein expression profiles
Show heterogeneity
How can the heterogeneity of vascular cells be directly observed?
Single cell RNAseq
Gene expression profile created to show which genes (and therefore properties) a cell is expressing
Seurat clustering: each dot is a cell, cells are grouped according to similarity of gene expression
How do endothelial cells directly control tissue-specific cell functions?
Endothelial cells produce Angiocrine factors - 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
How are new blood vessels formed?
Angiogenesis - formation of neo-vessels from pre-existing blood vessels
What drives and regulates angiogenesis?
Wide array of growth factors and signalling pathways
Pathways depend on dynamic regulation of gene expression in endothelial cells
Normaly quiescent, angiogenesis can be induced in ECs by vascular endothelial growth factor (VEGF) and other signalling molecules
What are the physiological processes which involved angiogenesis?
Development
Menstrual cycle
Wound healing
What pathologies does angiogenesis play a significant role in?
Cancer
Atherosclerosis
Retinopathies
Chronic inflammatory diseases
Ischaemic diseases
Vascular malformations
(not even close to a comprehensive list)
What is the relationship between angiogenesis and cancer growth?
Small tumours receive oxygen and nutrients by diffusion from host vasculature
Large tumours need new vessels - secrete angiogenic factors - stimulates neo-vessel formation in endothelial cells in adjacent vessels:
The Angiogenic Switch
Tumour vasculature facilitates growth and metastasis
What is the consequence of the relationship between cancer growth and angiogenesis in clinical treatments?
Anti-angiogenic drugs used in combination with chemotherapy
Used for a number of solid-type tumours
How do blood vessels help trigger haemostasis?
Damage to endothelial cells triggers the release of clotting factors (simplified explanation)
What is Von Willebrand Disease (VWD)?
Most common hereditary bleeding disorder due to decrease or dysfunction of von Willebrand Factor (VWF)
Characterised mainly by mucosal bleeding
Most forms mild
Replacement therapy effective in most cases
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)
What effect do cardiovascular risk factors have on the endothelium?
Cardiovascular risk factors (such as mechanical stress, high BP, high glucose, smoking, viruses etc…) lead to chronically activated epithelium
Leads to thrombosis, senescence, leukocyte recruitment, increased permeability
All these things facilitate development of atherosclerosis
What is the initial step in the pathogenesis of atherosclerosis?
Endothelial dysfunction
Which molecules increase in endothelial dysfunction in atherosclerosis?
Prostacyclin
Platelet-derived growth factor
Angiotensin II
Endothelin
What is the role of leukocytes in the early stages of atherosclerosis?
They adhere to and migrate into the artery wall, contributing to fatty streak formation after absorbing OxLDL and becoming foam cells
What cellular changes occur during the formation of fatty streaks in atherosclerosis?
Smooth muscle migration, foam cell formation, and T cell activation
Name adhesion molecules involved in atherosclerosis
E-selectin, P-selectin, intercellular adhesion molecule 1, and vascular-cell adhesion molecule 1
What marks the transition from a fatty streak to an advanced lesion in atherosclerosis?
The formation of a fibrous cap that walls off the lesion from blood flow
What does the fibrous cap cover in advanced atherosclerotic lesions?
A mix of leukocytes, lipids, and cellular debris, often forming a necrotic core
What is the purpose of the fibrous cap in atherosclerosis?
It acts as a type of healing response, attempting to stabilize the lesion by separating it from blood flow
How do macrophages contribute to advanced atherosclerotic lesions?
They accumulate in the lesion, promote inflammation, and release factors that contribute to tissue damage
How does the fibrous cap affect the stability of an atherosclerotic lesion?
While it initially stabilizes the lesion, factors that weaken the cap over time can lead to rupture
Outline the leukocyte adhesion cascade
Capture
Rolling - slow rolling - arrest
^During which activation takes place
Adhesion strengthening, spreading
Intravascular crawling
Paracellular or transcellular transmigration
How are blood leukocytes recruited into venules?
Recruitment of blood leukocytes into tissues normally takes place during inflammation
Leukocytes adhere to the endothelium of post-capillary venules and transmigrate into tissues
Outline leukocyte recruitment 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
How does an activated endothelium lead to LDLs entering the subendothelial space?
The endothelium regulates permeability: the 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
Lipoproteins (LDL) enter the subendothelial space, get oxidized LDL (OxLDL) and further promote endothelial activation
Why is the shear stress different in different parts of the vascular system?
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 nonuniform and irregular distribution of low wall shear stress
What effects does laminar blood flow exert on vascular endothelium?
Anti-thrombotic, anti-inflammatory factors
Endothelial survival
Inhibition of SMC proliferation
Nitric oxide (NO) production
What effects does disturbed blood flow exert on vascular endothelium?
Thrombosis, inflammation (leukocyte adhesion)
Endothelial apoptosis
SMC proliferation
Loss of Nitric oxide (NO) production
What are the effects of nitric oxide in the vascular system?
What are the effects of angiogenesis in cardiovascular disease?
Angiogenesis promotes plaque growth
BUT
Therapeutic angiogenesis prevents damage post-ischaemia
