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Cardiovascular system > Vascular Endothelium 2 > Flashcards

Vascular Endothelium 2 Flashcards

1
Q

What is the vascular system relevant to

A

Every disease

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2
Q

What is atherosclerosis a response to

A

Atherosclerosis is a stereotypic arterial response to injury {756}
Exact pathology determined by nature and duration of the stimulus
Atherosclerosis as a syndrome

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3
Q

Describe the characteristics of atherosclerosis

A

Atherosclerosis is a build up of fibrous and fatty material inside the arteries and underlies CVD.

  • Atherosclerosis is a chronic inflammatory disease.
  • It is also a very slow disease – can take up to 4 decades to form and then rupture
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4
Q

List some of the chronic stimuli for the aorta

A

Cholesterol, smoking, high BP

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5
Q

Describe the stages involved in the development of atherosclerosis

A

Endothelial dysfunction
Fatty streak formation
Formation of an advanced complicated lesion of athersclerosis

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6
Q

Describe endothelial dysfunction atherosclerosis

A

Endothelial Dysfunction in Atherosclerosis. The earliest changes that precede the formation of lesions of atherosclerosis take place in the endothelium. These changes include 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, including L-selectin, integrins, and platelet–endothelial-cell adhesion molecule 1, and the up-regulation of endothelial adhesion molecules, which include E-selectin, P-selectin, intercellular adhesion molecule 1, and vascular-cell adhesion molecule 1; and migration of leukocytes into the artery wall, which is mediated by oxidized low-density lipoprotein, monocyte chemotactic protein 1, interleukin-8, platelet-derived growth factor, macrophage colony-stimulating factor, and osteopontin.

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7
Q

Describe the formation of the advanced, complicated lesion of atherosclerosis

A

Formation of an Advanced, Complicated Lesion of Atherosclerosis. As fatty streaks progress to intermediate and advanced lesions, they tend to form a fibrous cap that walls off the lesion from the lumen. This represents a type of healing or fibrous response to the injury. 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 as those listed in Figures 1 and 2. The principal factors associated with macrophage accumulation include macrophage colony-stimulating factor, monocyte chemotactic protein 1, and oxidized low-density lipoprotein. The necrotic core represents the results of apoptosis and necrosis, increased proteolytic activity, and lipid accumulation. The fibrous cap forms as a result of increased activity of platelet-derived growth factor, transforming growth factor ß, interleukin-1, tumor necrosis factor , and osteopontin and of decreased connective-tissue degradation.
Angiogenesis also occurs

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8
Q

How does a fatty streak appear

A

As a yellow streak

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9
Q

What happens in fatty streak formation

A 
Smooth muscle migration
Foam cell activation
T cell activation
Platelet adherence and activation
Leukocyte adherence and entry
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10
Q

Which blood vessels consists of 3 layers

A

Blood vessels consist of THREE layers (except for capillaries and venules):

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11
Q

Describe the 3 layers of the blood vessels

A
  1. Tunica Intima – Endothelium.
  2. Tunica Media – Smooth Muscle Cells (VSMCs).
  3. Tunica Adventitia – Vasa Vasorum, Nerves.
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12
Q

Describe the Tunica Media

A

Consists of smooth muscle, then elastic membrane

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13
Q

Describe the Tunica Intima

A 
Inwards- Outwards
Endothelium 
Basement Membrane
Lamina Propria (smooth muscle and connective tissue)
Internal elastic membrane
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14
Q

Describe the Vasa Vasorum

A

This is a network of small blood vessels that supply the walls of larger blood vessels.

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15
Q

Describe the growth of endothelial cells

A

Single monolayer of cells, they grow in 2D and not 3D due to cellular communication (they send signals about their growth)

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16
Q

What is the role of the Human Cell Atlas

A

To sequence the transcriptome and genome of every cell in the body

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17
Q

What are the functions of the endothelia

A
  • Angiogenesis.
  • Thrombosis and Haemostasis.
  • Inflammation.
  • Angiogenesis.
  • Vascular tone permeability
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18
Q

List the matrix products and growth factors of the endothelia that result in angiogenesis

A

Growth factors:
Insulin like growth factors
Transforming growth factors
Colony Stimulating growth factors

Matrix products:
Fibronectin
Collagen
Laminin
Proteoglycans
Proteases
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19
Q

List the inflammatory mediators and adhesion molecules involved in inflammation

A

Adhesion molecules:
ICAMs
VCAMs
Selectins

Inflammatory mediators:
Interleukins 1,6,8
Leukotrienes
MHC 2

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20
Q

List the antithrombotic factors released by the endothelium

A 
prostacyclin
thrombomodulin
antithrombin
plasminogen activator
heparin
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21
Q

List the procoagulant factors released by the endothelium

A 
von Willebrand factor
thromboxane A2
thromboplastin 
factor V
Platelet activating factor
Plasminogen activator inhibitor
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22
Q

List the vasodilator and vasoconstrictor factors involved in vascular tone

A

Vasodilator:
Nitric Oxide
Prostacyclin

Vasoconstrictor:
ACE
thromboxane A2
leukotrienes
free radicals 
endothelin
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23
Q

At rest, what is the essential feature of the endothelium

A

Keeps the balances to pro and anti, essential to life.

HEALTHY STATE – Endothelia tend to maintain an anti-thrombotic, anti-inflammatory and anti-proliferative state

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24
Q

Describe the state of the resting endothelium at rest

A
  • UNHEALTHY STATE – If the endothelia become damaged etc. they flip to the reverse of the above.
  • In atherosclerosis, this unhealthy state is CHRONIC as it is a chronic inflammatory disease à problems.
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25
Q

Describe some of the stimuli that can chronically activate the endothelium and lead to atherosclerosis

A 
Thrombosis
Senescence 
oxLDL
Glucose
High BP
Permeability and Leukocyte recruitment
Mechanical stress
Viruses
Inflammation
Smoking
Hypercholesterolaemia 
(e.g. oxidatively modified lipoproteins
Diabetes mellitus / metabolic syndrome
Hypertension 
(e.g. ANG-II & ROS
Sex hormonal imbalance
(e.g. oestrogen deficiency & menopause )
Proinflammatory cytokines
(e.g. IL-I & TNF)
Oxidative stress 
Infectious agents 
(e.g. bacterial endotoxins & viruses)
Environmental toxins
(e.g. cigarette smoke and air pollutants)
Haemodynamic forces
(e.g. disturbed blood flow)
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26
Q

Describe the characteristics of the vascular endothelium

A
  • Endothelia form single layers of cells and when they divide, they need to know to do this. In forming a monolayer, they undergo contact inhibition.
  • Normally, once formed, the cells are stable and not a lot of new cells grow except in angiogenesis or healing
27
Q

Describe Leukocyte recruitment in atherosclerosis

A

Recruitment of blood leukocytes into tissues takes place normally 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
Newly formed post-capillary venules at the base of developing lesions provide a further portal for leukocyte entry
Monocytes migrate into the subendothelial space differentiate into macrophages

28
Q

Describe leukocyte recruitment

A

Rolling and Activation

  • At inflammation, endothelium becomes activated and expresses ligands for the leukocytes.
  • Selectins on the leukocyte begin to weakly interact with the endothelium which initiates ROLLING. L-Selectins on leukocytes bind to E and P selectins on the endothelium.

Firm Adhesion
* Internal signals activate the integrins on the surface of the leukocyte, switching the integrins to a ‘high-affinity’ state.
* Integrins bind strongly to the endothelium and leukocyte adheres and transmigrates.
Integrins on the leukocyte(LFA-1, VLA-4)
bind to VCAM-1 and ICAM-1 on the endothelium.

29
Q

How do the leukocytes cross the post-endothelial venule

A

The flatten out and move across the PEV paracellularly and transcellular

30
Q

What ensures that the endothelial cells only grow in 2D

A
  • Endothelia form single layers of cells and when they divide, they need to know to do this. In forming a monolayer, they undergo contact inhibition- when the contact reaction takes place, the cells enter quiescence.
  • Normally, once formed, the cells are stable and not a lot of new cells grow except in angiogenesis or healing..
31
Q

Why is it difficult to design drugs that treat problems associated with the vascular endothelium

A

Not all endothelia are the SAME. There are subtle differences in the glycoproteins etc.

32
Q

Describe endothelial junctions

A
  • Leukocytes transmigrate by squeezing between endothelial junctions.
  • V-cadherin is present at all junctions.
  • At a junction, both endothelial cells’ surface proteins bind in a homophilic way.
  • This binding creates a zipper which some molecules can unzip and pass through.
33
Q

Describe the differences in structures of the capillaries and post-capillary venules

A

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

34
Q

Describe the basic structure of arteries and relate this to the problem seen in atherosclerosis

A

Artery: three thick layers, rich in cells and extracellular matrix.

  • In atherosclerosis, the leukocyte CANNOT pass through the whole thickness of the vessel so it gets trapped.
  • Normally, transmigration occurs in the post-capillary venules where the leukocyte can pass through, meet the basement membrane and chew through it with it’s enzymes but in the arteries, it cannot pass full thickness. However in atherosclerosis, the leukocytes get stuck in the basement membrane.
35
Q

What is meant by vascular permeability

A

The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa

36
Q

What are the consequences of increased vascular permeability

A
  • Increased permeability also results in leakage of plasma proteins from the blood, through the endothelial junctions and into the sub-endothelial space.
  • In this layer, the ‘sticky’ proteoglycans can trap the plasma proteins and the leukocytes.
    Can result in oedema
37
Q

Describe lipoprotein trapping and oxidative modification

A

The activated endothelium becomes more permeable to Lipoproteins, especially LDL.
LDL moves across the endothelium and binds to proteoglycan (by oxidation) in the sub-endothelial layer, where it gets ‘stuck’.
The pro-oxidative environment is created by secretions from macrophages.
4. Macrophages phagocytose the oxLDLs forming Foam Cells- fatty streak formation.
5. Chronic inflammation begins.

38
Q

Where do atherosclerotic plaques preferentially form

A

At bifurcations and curvatures.

39
Q

Describe Laminar flow

A

Streamlined, outermost layer moving slowest and centre moving fastest

40
Q

Describe Turbulent flow

A
  • Turbulent flow: Interrupted with rate of flow exceeding critical velocity presenting with rough eddy currents.
    Speed of fluid is continuously undergoing changes in both magnitude and direction
41
Q

Describe the protective effects of laminar flow

A

Laminar blood flow promotes antithrombotic factors, anti-inflammatory factors, nitric oxide production, inhibition of SMC proliferation.
It protects Nitric Oxide.

42
Q

Describe the effects of turbulent flow

A

Disturbed blood flow promotes coagulation, leukocyte adhesion, SMC proliferation, endothelial apoptosis and reduced nitric oxide production.
Atherosclerosis tends to occur at bifurcations due to turbulent flow

43
Q

Describe the role of laminar flow in reducing the risk for CVD

A

As Laminar blood flow PROMOTES endothelial cell survival with high shear stress, risk of atherosclerosis is reduced

44
Q

Describe the multiple protective effects of NO on the vascular endothelium

A

Reduces release of superoxide particles.
Dilates blood vessels
Inhibits monocyte adhesion
Reduces platelet activation
Reduces oxidation of LDL (major component of plaque)
Reduces proliferation of SMC in Vascular endothelium

45
Q

Describe the formation of early atherosclerotic lesions

A

Early lesions of atherosclerosis in the human carotid artery develop in the area of a major curvature (carotid sinus) exposed to low time-average shear stress, a high oscillatory shear index, and steep temporal and spatial gradients. Endothelial cells at this site display an atheroprone phenotype, which promotes a proinflammatory milieu driven by the priming of the NF-κB signaling pathway, which is then perpetuated in response to subendothelial apoB LPs. NF-κB activation promotes the entry of blood-borne monocytes (blue cells) through the junctions of endothelial cells (orange cells) into the intima, and there, monocytes differentiate into macrophages (red cells).

46
Q

Describe the epigenetic effects of laminar flow

A

In contrast, arterial geometries that are exposed to uniform laminar flow evoke an atheroprotective endothelial cell phenotype driven by the transcriptional integrators KLF2 and KLF4. This atheroprotective endothelial phenotype, together with a decrease in LP retention, promotes an antiinflammatory and antithrombotic environment that affords relative protection from atherosclerotic lesion development. KLF2,4 are also transcription factors for the eNOS gene.

47
Q

What is meant by epigenetics

A

functionally relevant, inheritable changes to the genomethat do not involve a change in thenucleotide sequence, which affect gene expression

48
Q

Describe the three key epigenetic mechanisms

A

There are three key epigenetic mechanisms that regulate gene expression (i) methylation of CpG islands, mediated by DNA methyltransferases, (ii) histone protein modifications and (iii) microRNAs. The various epigenetic modifications control gene activation and silencing affecting gene expression.

49
Q

How does the genome adapt to developmental and environmental cues

A

The genome adapts to developmental or environmental cues through modification of DNA itself (e.g. methylation) or of proteins that associate with DNA (e.g. histones) .
Epigenetic processes are essential for development and differentiation, and can also arise under the influence of the environment

50
Q

Can epigenetic pathways be targeted by drugs

A

yes

51
Q

Describe how stable flow can regulate endothelial epigenetic pathways

A

Stable flow (s-flow) downregulates expression of DNA methyltransferases (DNMTs), which allows the promoter of antiatherogenic genes, such as Klf4 and HoxA5, to remain demethylated, enabling their expression.

52
Q

Describe how disturbed flow can regulate endothelial epigenetic pathways

A

Disturbed flow (d-flow) upregulates DNMT expression, leading to hypermethylation of the promoter of antiatherogenic genes, such as Klf4 and HoxA5, repressing their expression.

53
Q

What is meant by angiogenesis

A

Angiogenesis is the sprouting of new vessels from the endothelial lining of preexisting vessels. Angiogenesis has long been thought to represent the principal paradigm for neovascularization to maintain homeostasis and for co-optation via the angiogenic switch for tumor growth

54
Q

Describe the Janus paradox

A

The Janus Paradox The idea that angiogenesis plays a beneficial but also detrimental role for the cardiovascular system.

  • Good – People who suffer from acute MI obtain fibrotic heart tissue that develops into heard failure BUT using therapeutic angiogenesis, we can prevent tissue damage by forming new vessels to supply these areas.
  • Bad – angiogenesis promotes atherosclerotic plaque formation as degraded products in the necrotic core simulate hypoxia which stimulates proliferation of the vaso Vasorum (little vessels) which are thin. These thin vessels are then more likely to break.
55
Q

Describe the characteristics of angiogenesis

A
  • Angiogenesis is totally controlled by endothelial cells and has a role in atherosclerosis.
  • Importantly, angiogenesis has a negative role in maintaining cancer growth.
  • Hypoxic tissues release chemicals that activate ECs and triggers them to differentiate to ‘tip’ cells which control formation of the blood vessel. Pericytes then aid growth.
  • Vascular Endothelium Growth Factor (VEGF) plays an important role in angiogenesis.
56
Q

How can angiogenesis promote the formation of the atherosclerotic plaque

A

Angiogenesis at the base of the plaque- growth of plaque, abnormal- leukocytes enter- plaque growth.

57
Q

What do blood vessels form before

A

Tissues

58
Q

Describe therapeutic angiogenesis

A

Another path for blood to travel, overcoming the block.

59
Q

What is meant by senescence

A

Cellular senescence: growth arrest that halts the proliferation of ageing and/or damaged cells.

Senescence is a response to stress and damage.
Senescent cells have distinctive morphology and acquire specific markers (e.g. b-gal)

60
Q

What is good about senescence

A

Prevents the transmission of damage to daughter cells.

Replicative senescence: the limited proliferative capacity of human cells in culture.

61
Q

What are the consequences of senescence

A

Senescent cells are pro-inflammatory and contribute to many diseases.

62
Q

Describe how senescence can contribute to atherosclerotic plaque progression

A
  • This is a way of making sure damaged cells don’t take over and is considered the body’s defence against cancer.
  • However, senescent cells (growth arrested cells) can develop a pro-inflammatory response.
  • Endothelial senescence can be induced by CV risk factors such as oxidative stress (this means it DOES NOT CAUSE atherosclerotic plaque formation) and as the cells are pro-inflammatory and pro-thrombotic therefore, they can contribute to atherosclerotic plaque progression.
63
Q

Describe the telomeric-dependent mechanisms of senescence

A

Senescence was initially considered to reflect the finite capacity for division that normal diploid cells exhibit when propagated in culture, hence the term “replicative senescence.”
At the molecular level senescence resulting from successive rounds of cell division has been linked to the progressive shortening and eventual dysfunction of telomeres, the physical ends of chromosomes. In mammalian cells telomeres consist of a repeated DNA sequence (TTAGGG) that extends over a length of several thousand base pairs and associates to an array of specialized telomere binding proteins. Synthesis of telomeric DNA requires the presence of telomerase, a ribonucleoprotein complex that catalyses the addition of TTAGGG repeats to the 3’-end of the DNA chain. The majority of human adult somatic cells either lack or have very low levels of telomerase (25). Under these conditions, and due to the inability of conventional DNA polymerases to replicate the end of the lagging strand, DNA synthesis during cell division results in a gradual loss of telomeric DNA (68). In addition, due to its high GGG content, telomeric DNA is particularly susceptible to oxidative damage and the generation of single strand breaks. Accordingly, the rate of telomere erosion is also greatly affected by the oxidative burden of the cell (91). Telomere erosion eventually compromises its functional integrity and leads to the induction of a DNA damage checkpoint response that halts the cell-cycle permanently (15).

Cardiovascular system (19 decks)

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