Vascular Disease: Atherosclerosis Flashcards

1
Q

Causes and clinical symptoms of Arterial blockage

A

Caused by formation of lesions and plaques building up in the arteries

Clinical symptoms:
- heart attack, heart failure, stroke, pulmonary blockage, peripheral arterial disease, coronary heart disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Steps of Atherosclerosis

A

1) normal
2) fatty streak
3) fibrous plaque (largely consisting of immune cells)
4) complicated lesion (cellular debris, cholesterol, foam cells, immune cells…)
5) Destabilisation/rupture causing clot

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Arterial blood clotting (‘plugging up’ the artery)

A

Sudden rupturing of an atherosclerotic plaque causes a thrombus which can cause heart attack/stroke (if in brain)

  • plaque comes as a result of vascular dysfunction
  • platelets in thrombus aim to ‘plug up’ the ruptured endothelial cell wall/plaque but also plug up the entire artery
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

How blood-lipid levels are linked to atherosclerosis (AS)

A

lipid particles = phospholipid monolayer (apo-lipoproteins) + central core of cholesteryl esters & non-polar lipids

  • cholesterol levels = proportional to incidence of AS
  • blood cholesterol >4.8-5.1 mmol/L = unhealthy (high levels = heart attacks)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Cholesterol structure and uses

A

A 27-carbon amphipathic molecule

  • 4 ring steroid nucleus
  • OH group on C3
  • Amphipathic: polar OH, hydrophobic tail

Uses (found largely in higher eukaryotes):

  • biological membranes
  • Vit D synthesis, Ca homeostasis
  • steroid hormone biosynthesis
  • bile synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

LDL levels linked to AS

A

Low Density Lipoproteins = key cholesterol carriers circulating in blood stream

In high pressure arteries, LDL can get pushed into artery vessel walls & accumulate (leading to AS)

Defects in LDL receptors can increase risk of AS:

  • LDLRs normally remove LDL from blood
  • defective LDLRs = increased blood-LDL concentrations
  • Increased LDL concentration means more likely to enter arterial walls
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How LDL accumulation in arterial walls leads to AS

A

1) ROS modify LDL into oxLDL in the artery wall
2) oxLDL promotes endothelial cells to express leukocyte adhesion molecules (VCAM1), recruiting monocytes and T cells
3) Monocytes differentiate into macrophages (due to MCSF) that engulf/uptake oxLDL
4) excessive oxLDL uptake turns macrophage into Foam cells which die and accumulate
5) Foam cells promote production of more pro-inflammatory signal molecules (TL9 binding promotes IFNg secretion + IL2,6 and 1.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Normal LDLR-LDL trafficking

A

LDLR-LDL complex gets endocytosed and is delivered to early endosomes where LDLR-LDL uncouple
- LDLR recycles to cell surface, LDL is transported to late endosomes/lysosomes where it’s broken down into cholesterol

Self-regulation: cholesterol regulates transcription of LDLR gene

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How cholesterol regulates transcription of LDLR gene

A

Cholesterol sensing proteins (SREBPs) located in the ER and Golgi respond to free cholesterol in the cell

  • the proteins are cleaved and enter the nucleus to act as transcriptional coregulators (e.g. inhibiting LDLR synthesis if high cholesterol levels detected)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Atherosclerotic plaque initiation:

LDL modification and leukocyte differentiation

A

LDL is modified into mLDL & oxLDL

  • modified LDLs are recognised by vascular cells to trigger pro-inflammatory responses, recruiting monocytes

Leukocytes/monocytes enter arterial wall
- macrophage differentiation –> foam cell formation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Monocyte recruitment

Macrophage becoming foam cells

A

Monocytes circulating the blood stream enter the Intima of blood vessel via endothelial lining (Trans-Endothelial Migration, TEM)
- Monocytes detect macrophage-activating factors and differentiate

Macrophage bind & engulf oxLDL & mLDL

  • become fat-rich and begin to die
  • fat-engorged macrophage differentiate into foam cells (very large cells)
  • foam cells dies and form core of lesion/plaque
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Vascular Smooth Muscle Cells (VSMCs)

A

important in vascular constriction and relaxation (blood pressure)

contribute to plaque formation through cellular apoptosis and remodelling around damaged areas of artery

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Platelets regulate blood clot (thrombus) formation

A

Platelets, produced by magakaryocytes, interact with vasculature via cell surface receptors

  • fibrinongen and VWF binding is critical for platelet aggregation/clot formation
  • leukocytes and endothelial cells also interact with platelets
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How inflammation alters the endothelial-leukocyte adhesion dynamics

A

Increased inflammation (by infection too) increases endothelial-leukocyte adhesion meaning more monocytes and an increased chance of AS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Trans-Epithelial Migration (TEM)

A

a.k.a. Diapedesis: Leukocytes interacting with endothelium to enter tissues nearby

1) Tethering and rolling
2) Activation
3) Firm adhesion
4) Transmigration
- leukocyte squeezes between 2 endothelial cells
- EC-EC connections are temporarily disrupted

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Endothelial cell’s role in regulating blood pressure and clot formation

A

Signalling pathways activate the endothelial Nitric Oxide Synthase (eNOS) enzyme which converts L-arginine into Nitric Oxide (NO) gas

  • NO enters smooth muscle causing immediate relaxation & vessel dilation
  • NO enters blood stream to inhibit platelets and TEM
17
Q

Benefits of Angiogenesis in Atherosclerosis

A

Stimulates endothelial function & blood vessel regeneration

Promote tissue repair

Regulate activity of surrounding cells and tissues

Promotes collateral formation
- ‘B-roads’ around the area of atherosclerosis help blood flow and reduce pressure

18
Q

Dangers of Angiogenesis in Atherosclerosis

A

Can destabilise a ‘stable’ plaque

- collateral formation near plaque can grow causing destabilisation and rupture

19
Q

Peripheral Arterial Disease (PAD)

A

Results from atherosclerosis in peripheral arteries reducing blood flow to limbs

  • risk of sores, gangrene and infection
  • risk of amputation and death
20
Q

Cures for PAD

A
  • Removing blockage
  • Inserting a stent helps blood flow
  • vein by-pass graft
  • inject agents (e.g. VEGFA) to promote angiogenesis
21
Q

Pre-eclampsia

A

Dysfunction in VEGF signalling causes sudden rise in blood pressure
- affects 1 in 10 pregnancies: mild to severe forms

Involves elevated levels of soluble VEGFR1 which strongly binds to VEGFA

  • VEGFA can’t bind to VEGFR2 which is needed to produce NO
  • results in a high blood pressure & vasoconstriction (narrowed umbilical cord)
22
Q

Potential Treatments for Pre-eclampsia

A

No obvious cures exist and there are many concerns about a drug affecting embryo development

possible treatments:

  • Heme Oxygenase-1 (HO-1) antagonises VEGFR1 levels via CO
  • Statins reduce blood pressure and stimulate HO-1

Stem cell treatment?
- using endothelial, myeloid and smooth muscle progenitors