🫀🫁Cardio & Resp🫀🫁 - Vascular Endothelium

Question 1

What is the vascular system?

Answer 1

Question 2

What is the structure of the blood vessel wall?

Answer 2

Tunica adventitia
Tunica media
Tunica intima

Question 3

What is contained in the tunica adventitia?

Answer 3

Vasa nervosum - endothelial cells blood supply
Nerves

Question 4

What is contained in the tunica media?

Answer 4

External elastic membrane
Smooth muscle cells

Question 5

What is contained in the tunica intima?

Answer 5

Internal elastic membrane
Lamina propria (smooth muscle and connective tissue)
Basement membrane
Endothelium

Question 6

Which are the only vessels that don’t exhibit the three layer structure?

Answer 6

Capillaries and venules

Question 7

What are capillaries?

Answer 7

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

Question 8

What is the role of the endothelium in the vascular system?

Answer 8

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)

Question 9

What is contact inhibition?

Answer 9

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

Question 10

What happens to endothelial cells when there is damage to the vessel wall (re contact inhibition)?

Answer 10

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

Question 11

What is the lifespan of endothelial cells?

Answer 11

Long life - low proliferation rate
UNLESS
New vessels required - angiogenesis

Question 12

How do the properties of blood vessels vary in different areas of the body?

Answer 12

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

Question 13

How can the heterogeneity of vascular cells be directly observed?

Answer 13

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

Question 14

How do endothelial cells directly control tissue-specific cell functions?

Answer 14

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

Question 15

How are new blood vessels formed?

Answer 15

Angiogenesis - formation of neo-vessels from pre-existing blood vessels

Question 16

What drives and regulates angiogenesis?

Answer 16

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

Question 17

What are the physiological processes which involved angiogenesis?

Answer 17

Development
Menstrual cycle
Wound healing

Question 18

What pathologies does angiogenesis play a significant role in?

Answer 18

Cancer
Atherosclerosis
Retinopathies
Chronic inflammatory diseases
Ischaemic diseases
Vascular malformations
(not even close to a comprehensive list)

Question 19

What is the relationship between angiogenesis and cancer growth?

Answer 19

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

Question 20

What is the consequence of the relationship between cancer growth and angiogenesis in clinical treatments?

Answer 20

Anti-angiogenic drugs used in combination with chemotherapy
Used for a number of solid-type tumours

Question 21

How do blood vessels help trigger haemostasis?

Answer 21

Damage to endothelial cells triggers the release of clotting factors (simplified explanation)

Question 22

What is Von Willebrand Disease (VWD)?

Answer 22

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

Question 23

What is the role of VWF in angiogenesis?

Answer 23

Endothelial VWF controls blood vessel formation (angiogenesis) and integrity, partly by regulating growth factor signalling (VEGFR2; Ang-2)

Question 24

What effect do cardiovascular risk factors have on the endothelium?

Answer 24

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

Question 25

What is the initial step in the pathogenesis of atherosclerosis?

Answer 25

Endothelial dysfunction

Question 26

Which molecules increase in endothelial dysfunction in atherosclerosis?

Answer 26

Prostacyclin Platelet-derived growth factor Angiotensin II Endothelin

Question 27

What is the role of leukocytes in the early stages of atherosclerosis?

Answer 27

They adhere to and migrate into the artery wall, contributing to fatty streak formation after absorbing OxLDL and becoming foam cells

Question 28

What cellular changes occur during the formation of fatty streaks in atherosclerosis?

Answer 28

Smooth muscle migration, foam cell formation, and T cell activation

Question 29

Name adhesion molecules involved in atherosclerosis

Answer 29

E-selectin, P-selectin, intercellular adhesion molecule 1, and vascular-cell adhesion molecule 1

Question 30

What marks the transition from a fatty streak to an advanced lesion in atherosclerosis?

Answer 30

The formation of a fibrous cap that walls off the lesion from blood flow

Question 31

What does the fibrous cap cover in advanced atherosclerotic lesions?

Answer 31

A mix of leukocytes, lipids, and cellular debris, often forming a necrotic core

Question 32

What is the purpose of the fibrous cap in atherosclerosis?

Answer 32

It acts as a type of healing response, attempting to stabilize the lesion by separating it from blood flow

Question 33

How do macrophages contribute to advanced atherosclerotic lesions?

Answer 33

They accumulate in the lesion, promote inflammation, and release factors that contribute to tissue damage

Question 34

How does the fibrous cap affect the stability of an atherosclerotic lesion?

Answer 34

While it initially stabilizes the lesion, factors that weaken the cap over time can lead to rupture

Question 35

Outline the leukocyte adhesion cascade

Answer 35

Capture Rolling - slow rolling - arrest ^During which activation takes place Adhesion strengthening, spreading Intravascular crawling Paracellular or transcellular transmigration

Question 36

How are blood leukocytes recruited into venules?

Answer 36

Recruitment of blood leukocytes into tissues normally takes place during inflammation Leukocytes adhere to the endothelium of post-capillary venules and transmigrate into tissues

Question 37

Outline leukocyte recruitment in atherosclerosis

Answer 37

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

Question 38

How does an activated endothelium lead to LDLs entering the subendothelial space?

Answer 38

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

Question 39

Why is the shear stress different in different parts of the vascular system?

Answer 39

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

Question 40

What effects does laminar blood flow exert on vascular endothelium?

Answer 40

Anti-thrombotic, anti-inflammatory factors Endothelial survival Inhibition of SMC proliferation **Nitric oxide (NO) production**

Question 41

What effects does disturbed blood flow exert on vascular endothelium?

Answer 41

Thrombosis, inflammation (leukocyte adhesion) Endothelial apoptosis SMC proliferation **Loss of Nitric oxide (NO) production**

Question 42

What are the effects of nitric oxide in the vascular system?

Answer 42

Question 43

What are the effects of angiogenesis in cardiovascular disease?

Answer 43

Angiogenesis promotes plaque growth BUT Therapeutic angiogenesis prevents damage post-ischaemia