Vascular Endothelium

Question 1

What is the vascular system?

Answer 1

The vascular system is one of the largest and the most extensive networks in the body

Blood vessels are lined by endothelial cells.

When dysfunctional, the endothelium contributes to more diseases than any other organ

Question 2

Describe the basic structure of blood vessels

Answer 2

Three layers:
(except for capillaries and venules)

Tunica adventitia
Vasa vasorum, nerves

Tunica media
Smooth muscle cells

Tunica intima
Endothelium

Question 3

What happens in capillaries?

What are they formed by?

Answer 3

Capillaries is where the exchanges of nutrients and oxygen between blood and tissues occur
Capillaries and venules are formed by endothelium, supported by mural cells (pericytes) and a basement membrane

Question 4

What are the different types of blood vessel heterogeneity

Answer 4

Vascular and endothelial

Question 5

What do the majority of vessels in the body, microcirculation, consist of?

Answer 5

Endothelial cells surrounded by pericytes

Question 6

What properties do endothelial cells and pericytes have?

Answer 6

Endothelial cells (and pericytes) have organotypic (tissue-specific) properties and unique gene/protein expression profiles

Continuous non fenestrated. fenestrated and discontinuous

Question 7

Describe endothelial cells that line the vascular system

Answer 7

The Endothelium acts as a vital barrier separating blood from tissues
Very extensive: surface area > 1000 m2; weight >100 g
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)
In vivo, endothelial cells live a long life and have a low proliferation rate (unless new vessels are required: angiogenesis)
Endothelial cell regulate essential functions of blood vessels

Question 8

What functions of blood vessels and tissues does the endothelium control?

Answer 8

Vascular tone
Inflammation
Tissue homeostasis and regeneration
Permeability
Angiogenesis
Haemostasis & Thrombosis

Question 9

What are angiocrine factors?

Answer 9

Angiocrine factors from endothelial cells 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

Question 10

What is the most abundant cell type in the normal myocardium?

Answer 10

Endothelial cells

Question 11

What does single cell RNAseq do?

Answer 11

Single-cell RNA sequencingexamines thesequenceinformation from individualcellswith optimizednext-generation sequencingtechnologies.

Question 12

What is sprouting angiogenesis

Answer 12

The formation of new vessels by sprouting from existing vessels

Question 13

What is the physiology of sprouting angiogenesis?

Answer 13

Development
Menstrual cycle
Wound healing

Question 14

What is the pathology of sprouting angiogenesis?

Answer 14

Cancer
Chronic inflammatory diseases
Atherosclerosis
Retinopathies
Ischemic diseases
Vascular malformations

Question 15

What are the mechanisms of sprouting angiogenesis?***

Question 16

In vivo models of angiogenesis*

Question 17

Describe the neovasculature for tumor angiogenesis?

Answer 17

Tumors less than 1 mm3 receive oxygen and nutrients by diffusion from host vasculature.

Larger tumors require new vessel network. Tumor secretes angiogenic factors that stimulate migration, proliferation, and neovessel formation by endothelial cells in adjacent established vessels.

Newly vascularized tumor no longer relies solely on diffusion from host vasculature, facilitating progressive growth.

Question 18

What is the angiogenic switch

Answer 18

The angiogenic switch is a discrete step in tumour development that can occur at different stages in the tumour-progression pathway, depending on the nature of the tumour and its microenvironment

Question 19

What are tumour blood vessels?

Answer 19

irregularly shaped, dilated, tortuous
not organized into definitive venules, arterioles and capillaries
leaky and haemorrhagic, partly due to the overproduction of VEGF
perivascular cells often become loosely associated

Question 20

How is the homeostatic balance maintained in endothelial cells?*

Answer 20

Angiogenesis
Inflammation
Thrombosis & haemostasis
Vascular Tone
Permeability

Question 21

Is healthy endothelium anti-thrombotic and anti-inflammatory

Answer 21

Yes

Question 22

What is thromboinflammation ?

When does it occur?

Answer 22

Loss of the normal antithrombotic and anti-inflammatory functions of endothelial cells causes thrombosis with associated inflammation

Occurs in many disorders, including sepsis, ischemia-reperfusion injury ….

Question 23

How is endothelial homeostasis maintained in resting endothelium?

Answer 23

Anti-inflammatory
Anti-thrombotic
Anti-proliferative

Question 24

How is endothelial homeostasis maintained in activated endothelium?

Answer 24

ATHEROSCLEROSIS

Viruses
Smoking
Thrombosis
Senescence
Mechanical stress
Inflammation
High blood pressure
OxLDL
High glucose
Permeability
Leukocyte recruitment

Question 25

Describe the pathogenesis of Atherosclerosis: Response to injury model *

Answer 25

1. Endothelial Dysfunction in Atherosclerosis 2. Fatty-Streak Formation in Atherosclerosis 3. Formation of an Advanced, Complicated Lesion of Atherosclerosis

Question 26

What are mechanisms for endothelial dysfunction in the pathogenesis of atherosclerosis

Answer 26

Leukocyte recruitment Permeability Shear stress Angiogenesis

Question 27

Describe the leukocyte adhesion cascade* Describe Leukocyte recruitment in venules vs arteries

Answer 27

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

Question 28

Capillary vs post-capillary venule?

Answer 28

Capillary: endothelial cells surrounded by basement membrane and pericapillary cells (pericytes) Post-capillary venule: structure similar to capillaries but more pericytes

Question 29

Describe Vascular permeability

Answer 29

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

Question 30

How does lipoprotein trapping and oxidative modification work?

Answer 30

Lipoprotiens To lipoprotein oxidation To Foam cell To macrophage

Question 31

Why does atherosclerosis occur at branch points?

Answer 31

Atherosclerotic plaques occur preferentially at bifurcations and curvatures of the vascular tree The flow patterns and hemodynamic forces are not uniform in the vascular system

Question 32

?What are the different effects on the endothelium of laminar and Disturbed Flow?

Answer 32

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 33

What is the protective effect of laminar blood flow on the vascular endothelium?

Answer 33

Laminar blood flow promotes: anti-thrombotic, anti-inflammatory factors endothelial survival Inhibition of SMC proliferation Nitric oxide (NO) production Disturbed blood flow promotes: Thrombosis, inflammation (leukocyte adhesion) endothelial apoptosis SMC proliferation Loss of Nitric oxide (NO) production

Question 34

What are the Multiple protective effects of nitric oxide (NO) on the vascular endothelium

Answer 34

NO is essential for the health of the cardiovascular system Dilates blood vessels Reduces platelet activation Inhibits monocyte adhesion Reduces proliferation of SMC in the vessel wall Reduces release of superoxide radicals Reduces oxidation of LDL cholesterol (major component of plaque)

Question 35

What does angiogenesis do? What does therapeutic angiogenesis do?

Answer 35

Angiogenesis promotes plaque growth Therapeutic angiogenesis prevents damage post-ischemia

Question 36

Summary of role of endothelium in atherosclerosis development?

Answer 36

Leukocyte recruitment Leukocytes migrate into tissues through post-capillary venules during injury/inflammation In atherosclerosis, endothelial activation in large arteries causes leukocyte migration into the subendothelial space, where they accumulate and contribute to plaque development Blood flow Blood flow affects the phenotype of the endothelium Turbulent blood flow (often at branch points) causes chronic endothelial activation Atherosclerosis is most often found at arterial branch points Permeability Permeability is tightly controlled by endothelial cell-cell junctions Increased permeability to lipids contributes to early plaque formation Angiogenesis Angiogenesis is essential for development and physiological processes Pathological angiogenesis is associated with advanced atherosclerotic plaques