Vascular Endothelium Flashcards
What is the vascular system?
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
Describe the basic structure of blood vessels
Three layers:
(except for capillaries and venules)
Tunica adventitia
Vasa vasorum, nerves
Tunica media
Smooth muscle cells
Tunica intima
Endothelium
What happens in capillaries?
What are they formed by?
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
What are the different types of blood vessel heterogeneity
Vascular and endothelial
What do the majority of vessels in the body, microcirculation, consist of?
Endothelial cells surrounded by pericytes
What properties do endothelial cells and pericytes have?
Endothelial cells (and pericytes) have organotypic (tissue-specific) properties and unique gene/protein expression profiles
Continuous non fenestrated. fenestrated and discontinuous
Describe endothelial cells that line the vascular system
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
What functions of blood vessels and tissues does the endothelium control?
Vascular tone
Inflammation
Tissue homeostasis and regeneration
Permeability
Angiogenesis
Haemostasis & Thrombosis
What are angiocrine factors?
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
What is the most abundant cell type in the normal myocardium?
Endothelial cells
What does single cell RNAseq do?
Single-cell RNA sequencingexamines thesequenceinformation from individualcellswith optimizednext-generation sequencingtechnologies.
What is sprouting angiogenesis
The formation of new vessels by sprouting from existing vessels
What is the physiology of sprouting angiogenesis?
Development
Menstrual cycle
Wound healing
What is the pathology of sprouting angiogenesis?
Cancer
Chronic inflammatory diseases
Atherosclerosis
Retinopathies
Ischemic diseases
Vascular malformations
What are the mechanisms of sprouting angiogenesis?***
In vivo models of angiogenesis*
Describe the neovasculature for tumor angiogenesis?
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.
What is the angiogenic switch
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
What are tumour blood vessels?
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
How is the homeostatic balance maintained in endothelial cells?*
Angiogenesis
Inflammation
Thrombosis & haemostasis
Vascular Tone
Permeability
Is healthy endothelium anti-thrombotic and anti-inflammatory
Yes
What is thromboinflammation ?
When does it occur?
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 ….
How is endothelial homeostasis maintained in resting endothelium?
Anti-inflammatory
Anti-thrombotic
Anti-proliferative
How is endothelial homeostasis maintained in activated endothelium?
ATHEROSCLEROSIS
Viruses
Smoking
Thrombosis
Senescence
Mechanical stress
Inflammation
High blood pressure
OxLDL
High glucose
Permeability
Leukocyte recruitment
Describe the pathogenesis of Atherosclerosis:
Response to injury model *
- Endothelial Dysfunction in Atherosclerosis
- Fatty-Streak Formation in Atherosclerosis
- Formation of an Advanced, Complicated Lesion of Atherosclerosis
What are mechanisms for endothelial dysfunction in the pathogenesis of atherosclerosis
Leukocyte recruitment
Permeability
Shear stress
Angiogenesis
Describe the leukocyte adhesion cascade*
Describe Leukocyte recruitment in venules vs arteries
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
Capillary vs post-capillary venule?
Capillary: endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)
Post-capillary venule: structure similar to capillaries but more pericytes
Describe Vascular permeability
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
How does lipoprotein trapping and oxidative modification work?
Lipoprotiens
To lipoprotein oxidation
To Foam cell
To macrophage
Why does atherosclerosis occur at branch points?
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
?What are the different effects on the endothelium of laminar and Disturbed Flow?
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 is the protective effect of laminar blood flow on the vascular endothelium?
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
What are the Multiple protective effects of nitric oxide (NO) on the vascular endothelium
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)
What does angiogenesis do?
What does therapeutic angiogenesis do?
Angiogenesis promotes plaque growth
Therapeutic angiogenesis prevents damage post-ischemia
Summary of role of endothelium in atherosclerosis development?
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
