Vascular endothelium Flashcards
Describe the structure of the vascular system
(not just a distribution network)
- 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):
1. Tunica adventitia:
- Vasa vasorum
- nerves
2. Tunica media:
- Smooth muscle cells & (extrenal elastic membrane)
3. Tunica intima:
- Internal elastic membrane
- Lamina propria (smooth muscle and connective tissue)
- basement membrane
- endothelium
Describe the role & structure of capillaries
- Capillaries is where the exchanges of nutrients and oxygen between blood and tissues occur
- Capillaries and venules are formed by::
- endothelium (capillary endothelial cells)
- supported by mural cells (pericytes)
- and a basement membrane
- this is just a general overview of the structure- endothelial cells have heterogeneity
What are pericytes?
Pericytes are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body.
They are important for:
- blood vessel formation
- maintenance of the blood–brain barrier
- regulation of immune cell entry to the central nervous system (CNS)
- control of brain blood flow (constriction)
What is the role & structure of endothelial cells?
- Endothelial cells line the vascular system
- The Endothelium acts as a vital barrier separating blood from tissues
- Very extensive: surface area > 1000 m2; weight >100g
- 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)
- Endothelial cells directly control tissue-specific cell function- allow cells to have protein mediated interactions, e.g. to prevent overgrowth)
- In vivo, it is thought that 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/ processes are regulated by the endothelium?
- Vascular tone
- Angiogenesis
- Permeability
- Inflammation
- Haemostasis & thrombosis
What is the importance of angiocrine factors in endothelial cells?
- Endothelial cells directly control tissue-specific cell function
- All cells of the body are in contact with microvascular endothelial cells
- Angiocrine factors from endothelial cells are essential for the maintenance of tissue homeostasis and regeneration
- they are molecules found in blood vessels’ endothelial cells that can stimulate organ-specific repair activities in damaged or diseased organs.
- The angiocrine profile of each tissue-specific microvascular endothelium is different; conversely, the tissue-specific microenvironment influences the phenotype of endothelial cells
Endothelial cells are the most abundant cell type in the normal myocardium, true or false?
TRUE
How are vessel types categorised in terms of structure?
- They can either be continuous or discontinuous
- Of the continuous types, they can either be non-fenestrated or fenestrated
What are some examples of non-fenestrated (continuous) blood vessels in the body?
vessels that make up the:
- Muscle
- Lung
- Skin
- Blood brain barrier
What are some examples of fenestrated (continuous) blood vessels in the body?
Vessels that make up the:
- Kideny glomerulus
- GI tract
What are some examples of fenestrated (continuous) blood vessels in the body?
Vessels that make up the:
- Kidney glomerulus
- GI tract
What are some examples of discontinuous blood vessels in the body?
Vessels that make up the:
- liver
- marrow sinus
What is meant by “Single-cell RNA sequencing”?
- Single-cell RNA sequencingexamines thesequenceinformation from individualcellswith optimizednext-generation sequencingtechnologies
- Allows us to study a single cell that expresses a gene
What is the “Human Cell Atlas”?
The Human Cell Atlas is an international collaborative consortium that charts the cell types in the healthy body, across time from development to adulthood
What is meant by “sprouting angiogenesis”
“Sprouting angiogenesis is the growth of new capillary vessels out of preexisting ones”
- process is regulated by a wide array of growth factors and signalling pathways
- The list of endothelial molecules and pathways that modulate the formation of new vessels is constantly growing
- Most of these pathways depend on the dynamic regulation of gene expression in ECs, and are determined by a complex network of transcriptional regulators
When can “sprouting angiogenesis” occur?
Although normally quiescent, ECs (endothelial cells) have the ability to proliferate & form new vessels, either physiologically or due to some pathology:
Physiology:
- During development
- Menstrual cycle
- Wound healing
Pathology:
- Cancer
- Chronic inflammatory diseases
- Atherosclerosis
- Retinopathies
- Ischemic diseases
- Vascular malformations
Describe the process of “sprouting angiogenesis”
- Degradation & proliferation:
- Angiogenesis starts with the activation of endothelial cells by specific growth factors that bind to its receptors
- As a result, the extracellular matrix and basement membrane, surrounding the endothelial cells, are degraded locally by activated proteases
- Regulated by growth factors and inhibitors - Outgrowth/ Migration of ECs
- This allows the endothelial cells to invade into the surrounding matrix and, subsequently, to proliferate and migrate through the matrix
- EC proliferation & deposition of new ECM - Sprout fusion and lumen formation
By polarization of the migrating endothelial cells a lumen is created, and an immature blood vessel is formed - Stabilisation: perfusion & maturation
- The stabilisation of the immature vessels is established by recruitment of mural cells and generation of extracellular matrix.
- Decreased EC proliferation
- Increased pro-quiescent signals (prevent overgrowth)
Describe the effects of tumour angiogenesis
- Tumors less than 1 mm3 receive oxygen and nutrients by diffusion from host vasculature.
- Larger tumors require new vessel network. (cells in the centre experience hypoxia)
- 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.
- Tumour takes nutrients from the original blood vessel and is able to metastasis/ spread via this link
What is meant by the “angiogenic switch”?
The angiogenic switch is the term given to the point where the number or activity of the pro-angiogenic factors exceeds that of the anti-angiogenic factors, resulting in the angiogenic process proceeding, giving rise to new blood vessels from avascular/ dormant nodules into increased tumour growth and metastasis
- 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
Describe the features of 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
Explain the role of endothelium in haemostasis & thrombosis?
- Produces the procoagulant factors
- Healthy endothelium is anti-thrombotic and anti-inflammatory
- Loss of the normal antithrombotic and anti-inflammatory functions of endothelial cells causes thrombosis with associated inflammation: thromboinflammation
- Occurs in many disorders, including sepsis, ischemia-reperfusion injury
What are the causes of haemostasis inbalance that leads to activated endothelium/ atherosclerosis?
- Inflammation
- Mechanical stress
- Viruses
- Smoking
- high blood pressure
- OxLDL
- high glucose
- if stimulation is prolonged/ chronic= atherosclerosis
What happens to the endothelium during atherosclerosis?
atherosclerosis= arteries become clogged with fatty substances called plaques
- Endothelial dysfunction
- Increased endothelial permeability to lipoproteins and other plasma constituents, which is mediated by nitric oxide, prostacyclin, platelet-derived growth factor, angiotensin II, and endothelin
- up-regulation of leukocyte adhesion molecules
- up-regulation of endothelial adhesion molecules, which include E-selectin, P-selectin
- and migration of leukocytes into the artery wall, which is mediated by oxidized low-density lipoprotein - Fatty-streak formation
- leads to foam cell formation- form the atherosclerosis plug - Formation of an advanced, complicated lesion
- As fatty streaks progress to intermediate and advanced lesions, they tend to form a fibrous cap that walls off the lesion from the lumen (healing response)
- The fibrous cap covers a mixture of leukocytes, lipid, and debris, which may form a necrotic core
- These lesions expand at their shoulders by means of continued leukocyte adhesion and entry caused by the same factors
= Macrophage accumulation
Describe how leukocyte recruitment can lead to atherosclerosis
NORMALLY:
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 (form the atherosclerosis plug/ plaque)
Describe the effects of vascular permeability in atherosclerosis
The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
- In atherosclerosis increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space
- These plasma proteins: lipoprotein is trapped and oxidised to form foam cells
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
- So, these sites are exposed to low or disturbed blood flow, which exerts low/oscillatory shear stress on the vessel wall
(In straight parts of the arterial tree, blood flow is laminar and wall shear stress is high and directional)
What is better, high sheer stress of low sheer stress in the endothelium?
HIGH:
High sheer stress=
Laminar blood flow which promotes:
- anti-thrombotic, anti-inflammatory factors
- endothelial survival
- Inhibition of SMC proliferation
- Nitric oxide (NO) production
but low sheer stress=
disrupted blood flow which promotes:
- Thrombosis, inflammation (leukocyte adhesion)
- endothelial apoptosis
- SMC proliferation
- Loss of Nitric oxide (NO) production (reduced dilation; more likely to form plaques)
What is the role of NO in atherosclerosis?
PREVENTS ATHEROSCLEROSIS:
Multiple protective effects of nitric oxide (NO) on the vascular endothelium=
- Reduces oxidation of LDL (major component of plaque)
- Dilates blood vessels
- Reduces platelet activation
- Inhibits monocyte adhesion
- Reduces proliferation of SMC in the vessel wall
- Reduces release of superoxide radicals
