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Personalised Medicine - Cardiovascular > L7 - Physiology of the Vasculature I > Flashcards

L7 - Physiology of the Vasculature I Flashcards

1
Q

Why are blood vessels so important?

A

Changes in blood vessel underly the majority of cardiovascular diseases
Blood vessels supply nutrients, remove waste, provide gas exchange

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2
Q

What 4 diseases are caused by issues in blood vessels?

A 
Stroke 
- Block in blood vessels supplying or within the brain 
Myocardial infarction 
- Block in coronary artery 
Hypertension 
- Dysfunctional blood vessels - high blood pressure 
Pulmonary hypertension 
- Narrowing of pulmonary arteries
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3
Q

How does blood supply change during exercise?

A

↑ supply to muscles, lungs, heart

Driven by the sympathetic nervous system

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4
Q

How does blood supply change during digestion?

A

↑ supply to GI tract

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5
Q

How does blood supply change during thermoregulation?

A

↑ supply to skin to allow heat loss

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6
Q

What 2 disease are caused by dysfunction in artery walls~?

A

Atherosclerosis
- Initiated by dysfunctional blood vessels
Hypertension
- High blood pressure, due to blood vessel contraction regulation going wrong

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7
Q

Why do we need to understand vascular physiology?

A

Arterial contraction or relaxation results in changes in blood pressure
Understanding mechanisms → drug targets

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8
Q

Where does most control of blood vessel contraction and relaxation occur?

A

Arteries/arterioles

They are the main resistance vessels – small and muscular

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9
Q

What are the 4 layers of an artery wall?

A

Endothelium
Tunica media
Tunica intima
Tunica externa

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10
Q

What is the structure of the endothelium?

A

Thin layer of cells in direct contact with the blood – line the blood vessel
In direct contact with the blood to respond to circulating factor

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11
Q

What is the structure of the tunica media?

A

Smooth muscle, elastin, collagen matrix

Smooth muscle cells contract/relax to determine artery size

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12
Q

What is the structure of the tunica intima?

A

Connective tissue

Only in larger arteries - provides structural strength

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13
Q

What is the structure of the tunica external?

A

Elastic membrane - strong fibrous tissue to maintain vessel shape
Vessel wall stretches due to elasticity

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14
Q

What two things is smooth muscle contraction controlled by?

A

Circulating hormones

Local mediators released from the endothelium and sympathetic nerves

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15
Q

What are in contact with VSMCs?

A

Endothelial cells are directly in contact with VSMCs

Neurones are deeper in the artery wall to act directly on VSMCs

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16
Q

How do endothelial cells and VSMCs communicate?

A

Some direct contact between EC and VSMCs occurs via gap junctions

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17
Q

Where do gap junctions mostly occur?

A

Between VSMCs

Allow waves of calcium signalling across many cells so the artery wall contracts in a coordinated way

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18
Q

What happens if the endothelium is dysfunctional or activated?

A

You get disease

  • Dysregulated blood pressure
  • Initiate the events underlying atherosclerotic plaque formation
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19
Q

How do the endothelium and blood interact?

A

Endothelium is the first line to react to circulating factors, blood cells, pathogens
Have mechanical receptors on their surface that respond to blood flow - sheer stress

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20
Q

What is glycocalyx?

A

Sugar coating on surface of endothelium
Intact in non-activated endothelium
Anti-coagulant
- Prevents circulating cells from binding to
adhesion molecules on endothelial surface

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21
Q

What 3 things does the shedding of the glycocalyx occur in response to?

A

Injury, infection, inflammation (matrix metalloproteases released from immune cells)
oxLDL (lipid)
Disturbed blood flow (oscillatory shear stress)

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22
Q

What does shedding of the glycocalyx expose?

A

Adhesion molecules

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23
Q

What do adhesion molecules bind to once exposed and what does this lead to?

A

Adhesion molecules bind to glycans on circulating blood cells (monocytes, neutrophils and platelets)
Allows rolling/transmigration of blood cells along artery wall
- Key initiating events in atherosclerosis

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24
Q

What is blood flow like in straight vessels?

A

Blood flow exerts high shear stress force against the wall

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25
Q

What is blood flow like at branches/bends in vessels?

A

Blood flow becomes disturbed

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26
Q

Where do fatty plaques/activated endothelium mostly occur and why?

A

At the regions of disturbed blood flow

  • Shedding of the glycocalyx
  • Slowing of blood cells circulating in that region
  • Activated endothelium
  • Attracts monocytes and neutrophils to enter the artery wall
  • Atherosclerotic plaque formation
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27
Q

What signalling occurs within healthy endothelial cells?

A

Stimulated by Ach, histamine, bradykinin and 5-HT
Bind to GPCRs to mediate an increase in intracellular Ca
Activates eNOS which converts arginine to NO and citrullin
- NO is freely able to diffuse to act on adjacent cells

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28
Q

What does NO released from endothelial cells do to VSMCs?

A

Causes relaxation

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29
Q

What factor does high shear stress increase in endothelial cells?

A

NO

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30
Q

What other factors are there that don’t increase intracellular Ca but produce other signalling molecules that activate endothelium and cause a contraction of VSMCs?

A

Interleukin-1 - proinflammatory cytokine
Endotoxin - bacterial cell wall
Thrombin - from platelets
Disturbed blood flow

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31
Q

What do IL1, endotoxin, thrombin and disturbed blood flow all lead to an increase in?

A

Endothelin-1 or ROS –> act on adjacent VSMCs
Adhesion molecule expression –> increased monocyte/neutrophil/platelet interactions with endothelial cell –> transmigration across artery –> atherosclerosis
IL-8 production
COX-2 activity

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32
Q

On which side are factors secreted from endothelial cells to act on VSMC’s?

A

Basolateral surface (into arterial wall)

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33
Q

How is Ca maintained in a resting VSMC?

A

Intracellular Ca maintained low by Ca ATPase pumps in plasma membrane or sarcoplasmic reticulum

34
Q

What is the main way to cause an increase in Ca in VSMCs?

A 
Activating Ca channels in plasma membrane
Ca release from SR stores
Ca now present in cytoplasm
Binds to calmodulin to form a complex
Activates myosin light chain kinase
Phosphorylates myosin to activate it 
Actin cross-bridge cycle starts
35
Q

What is the alternative way to cause an increase in Ca in VSMCs?

A

Also have cell surface receptors that couple to increased IP3 levels
Activate receptors on the SR membrane to cause intracellular Ca release
Then activation of the myosin phosphorylation-contraction pathway

36
Q

What are the two differences between smooth muscle and skeletal muscle?

A

In VSMCs

  • Myosin needs to be phosphorylated to be active
  • Myosin phosphatase is always active - cell tends to be relaxed
    • Converts active myosin to inactive
37
Q

What are the two pathways that lead to VSMC contraction?

A

Increased IP3 production

Increased intracellular Ca

38
Q

What are the 5 GPCRs involved in VSMC contraction?

A 
Endothelin A/B
TP (prostanoid)
AT1 (angiotensin)
Histamine
Noradrenaline (alpha-adrenergic)
39
Q

What are the 4 Ca channels involved in VSMC contraction?

A 
Voltage sensitive (L-type)
Receptor operated (P2X)
TRP channels
Store operated (Ora1)
40
Q

What 3 signalling molecules are involved in VSMC relaxation?

A

cGMP
cAMP
Activation of K channels

41
Q

How does increased cGMP lead to VSMC relaxation?

A

Produced by guanylyl cyclase
Reduced intracellular Ca
Activate PKG –> activate myosin phosphatase –> more inactive myosin
Hydrolysed by phosphodiesterase’s

42
Q

How does increased cAMP lead to VSMC relaxation?

A

Produced by adenylyl cyclase

Reduced intracellular Ca Hydrolysed by phosphodiesterase’s

43
Q

How does activation of K channels lead to VSMC relaxation?

A

K efflux causes hyperpolarisation

Reduced intracellular calcium

44
Q

What are 3 K channels involved in VSMC relaxation?

A 
BK channels (large conductance)
SK channels (small conductance)	
Beta-agonists (via bg G-protein)
45
Q

How does NO also play a role in VSMC relaxation?

A

Released from endothelium

Activates guanylyl cyclase

46
Q

How do Gs coupled receptors also play a role in VSMC relaxation?

A 
Activates adenylyl cyclase 
E.g. 
- Beta-agonists
- Adenosine
- Prostaglandins
47
Q

Overall what 5 things does the apical side of the endothelium respond to?

A 
Circulating hormones 
Thrombin from platelets – injury
Cytokines and infectious stimuli 
Shear stress
Sympathetic neurotransmitters
These result in intracellular signaling in the endothelial cell either dependent on independent on Ca
48
Q

Overall what 4 mediators regulate VSMCs?

A

Nitric oxide
Prostanoids
Endothelin
Angiotensin II

49
Q

When is NO produced?

A

Produced by endothelium in response to a rise in Ca

50
Q

What does NO activate?

A

Freely permeable and diffuses to act on the VSMCs

Activates guanylyl cyclase –> cGMP –> PKG –> myosin phosphatase –> VSMC relaxation

51
Q

What does NO regulate?

A

Blood pressure and regional blood flow

52
Q

What increases NO production?

A

Many vasodilators (e.g. ACh)

53
Q

What regulates eNOS?

A

Shear stress regulates eNOS in resistance vessels via Akt

Phosphorylation of specific residues on eNOS regulates its sensitivity to calcium-calmodulin

54
Q

What does cGMP directly decrease?

A

Intracellular Ca

55
Q

What are caveoli?

A

Cholesterol rich microdomains
Caveoli contain clusters of eNOS enzymes
This means NO is produced close to cell surface to rapidly act on nearby VSMCs

56
Q

What does eNOS form complexes with?

A

eNOS is acetylated and complexes with Golgi and caveolae

57
Q

What 3 things is eNOS impaired by?

A

Smoking
High glucose and insulin
oxLDL

58
Q

How does smoking affect eNOS?

A

Interferes with eNOS acetylation –> loss of eNOS anchored to membrane
Reduces NO bioavailability

59
Q

How does high glucose and insulin affect eNOS?

A

Reduces eNOS phosphorylation

Reduces NO bioavailability

60
Q

How does oxLDL affect eNOS?

A

Depletes cholesterol from caveolae –> loss/displacement of eNOS
Disturbs eNOS function –> NO production dysregulated

61
Q

When are prostanoids produced?

A

By endothelium in response to a rise in Ca or ROS

62
Q

What do prostanoids activate

A

Activate COX 1/2 enzymes

Convert arachidonic acid to PGH2

63
Q

What is PGH2 converted into?

A

Converted into prostanoid derivatives depending on the enzymes present

  • Thromboxane A2
  • Prostaglandin E2
  • Prostaglandin I2
64
Q

PGH2 –> thromboxane A2 overview

A

Act on prostanoid thromboxane receptor (TP)

TP GPCR receptor –> PLC activation and IP3 production –> intracellular Ca release –> muscle contraction

65
Q

PGH2 –> prostaglandin E2 overview

A

Acts on prostaglandin E2 receptors (EP1-4) to either
Activate adenylyl cyclase –> increased cAMP –> PKA –> myosin phosphatase –> relaxation
Inhibit adenylyl cyclase –> decreases cAMP –> contraction

PGE2 effect depends on relative level of expression of EP receptor subtypes on the VSMCs - varies in different regions of the vasculature

66
Q

PGH2 –> prostaglandin I2 overview

A

Acts on the IP receptor

IP GPCR receptor –> adenylyl cyclase activation –> increased cAMP –> relaxation

67
Q

Endothelial cells produce ET-1 when exposed to?

A 
IL-1
Thrombin 
Glucose 
Ox-LDL
Insulin 
Angiotensin II
68
Q

How do endothelial cells produce endothelin?

A

Big endothelin is cleaved to ET-1 by Endothelin converting enzyme
oET-1 acts on VSMC at both ET A and B GPCR Gq receptors –> PLC activation and IP3 production –> intracellular Ca –> contraction

69
Q

What is the ET-1 negative feedback mechanism?

A

ET-1 acts back on endothelium via ETB receptors to block ECE activity
This increases Ca inside endothelium –> increases NO –> opposes VSMC contraction

70
Q

How is the ET-1 negative feedback mechanism of interest therapeutically?

A

Can specifically block ETA receptors and not ETB receptors to preferentially downregulate production of ET-1 and oppose its effects by maintaining the ETB negative feedback loop

71
Q

How is angiotensin II produced?

A

By the action of ACE on endothelial cells

72
Q

Where is ACE predominantly expressed?

A

On endothelial cells of pulmonary and renal vasculature

73
Q

What does ACE convert?

A

Converts circulating angiotensin –> angiotensin II –> AT1 receptors –> PLC activation and IP3 production –> intracellular Ca –> contraction

74
Q

What else do AT1 receptors also activate?

A

MAPK pathways in VSMC –> more persistent changes in signaling –> VSMCs more contractile

75
Q

How does ageing affect endothelial cells?

A

Cause changes where endothelial cells no longer able to regulate the VSMCs
All lead to increased blood pressure

76
Q

What 5 changes can ageing cause which all lead to an increase in blood pressure?

A 
Atherosclerosis
Damage to glycocalyx
Calcification
Loss of elastin
Decrease in NO
77
Q

What is atherosclerosis?

A

Build up on plaque over decades
Endothelial cells become physically more separated from the VSMCs.
- Loss of the coupling between endothelium and VSMCs
- Loss of regulation of the contractility of the artery
Results in raised blood pressure over decades
- Increase in blood pressure –> more strain on arteries –> loss of elasticity –> reinforce the loss of function, particularly in relation to relaxation

78
Q

What is damage to the glycocalyx caused by?

A

Hyperglycaemia
Hyperlipidaemia
Smoking
Sepsis and inflammation

79
Q

What is calcification?

A

Arteries become stiffer – less able to contract and relax

80
Q

What causes a decrease in NO?

A

Diet
Smoking
Hypoxia

Personalised Medicine - Cardiovascular (11 decks)

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