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CDL301 > Lecture 07 Vascular Physiology 1 > Flashcards

Lecture 07 Vascular Physiology 1 Flashcards

1. How blood vessel contraction is regulated physiologically 2. How do we target these mechanisms therapeutically in different diseases?

1
Q

Why is regulation of blood vessel contraction important? Give examples.

A

changes in blood pressure
important for directing blood supply to where oxygen and nutrients are needed in the body
exercise, digestion, thermoregulation

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2
Q

What happens when vascular physiology goes wrong?

A

atherosclerosis and hypertension

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3
Q

What initiates atherosclerosis?

A

dysfunctional blood vessels

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4
Q

What causes hypertension?

A

regulation of blood vessel contraction goes wrong

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5
Q

What are important physiological factors and functions of arteries?

A

strong - withstand high blood pressure
muscular - contract and relax
permeable - supply nutrients, remove waste and provide gas exchange

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6
Q

What are the main resistance vessels?

A

smaller muscular arteries

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7
Q

What are the layers of the artery?

A

tunica externa
external elastic membrane
tunica media - smooth muscle, elastin and collagen matrix
internal elastic membrane
tunica intima - endothelium and in larger arteries connective tissue

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8
Q

What is the function of the external/Adventitia elastic membrane?

A

very strong fibrous tissue

acts to maintain vessel shape

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9
Q

What is the function of elastin?

A

allows the vessel wall to stretch (elasticity)

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10
Q

What is the function of the smooth muscle?

A

contracts and relaxes to determine the size of the artery

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11
Q

What controls the state of the smooth muscle?

A

circulating hormone and local mediators from endothelium and sympathetic nerves

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12
Q

What is the function of endothelium?

A

located directly in contact with the blood to response to circulating factors, e.g. hormones

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13
Q

How do endothelium and vascular smooth muscle cells (VSMCs) communicate?

A

direct contact - gap junctions coupling cells together

also diffusion of mediators from endothelium

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14
Q

How do VSMCs communicate? Why is this important?

A

gap junctions between VSMCs allow effective calcium transport to allow coordinated contraction of the vessel

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15
Q

Why is endothelium so important?

A

it is the largest organ in the body lining every blood vessel
dysfunctional or activated endothelium leads to disease states
is the first line to react to circulating factors, blood cells and pathogens

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16
Q

What is an indicator that endothelia cells are healthy or inactive?

A

healthy glycocalyx

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17
Q

What does the glycocalyx consist of?

A

carbohydrate/sugar chains protruding from the apical surface of the endothelium

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18
Q

Why is the glycocalyx important?

A

acts as an anti-coagulant

prevents circulating cells from binding to adhesion molecules found on the surface of the endothelium

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19
Q

What can cause shedding of the glycocalyx?

A

injury, infection or inflammation
oxLDL (lipid)
disturbed blood flow (oscillatory shear stress)

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20
Q

What happens when the glycocalyx is damaged?

A

adhesion molecules on endothelium become exposed
circulating glycans on blood cells (monocytes, neutrophils, platelets) bind to adhesion molecules
blood cells roll along the artery wall, transmigrating
this initiates atherosclerosis

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21
Q

Where does disturbed blood flow occur? What does it cause?

A

branches of arteries

arteries bend

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22
Q

In healthy endothelium, what neurotransmitters can stimulate endothelium?

A

acetylcholine
histamine
bradykinin
serotonin

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23
Q

What happens in healthy endothelium signalling?

A

endothelium stimulated by neurotransmitters that bind to various receptors
this mediates an increase in intracellular calcium which activates endothelial Nitric Oxide Synthesis
eNOS converts arginine to nitric oxide and citrulline

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24
Q

What effect does nitric oxide (NO) have on VSMCs? How does this effect occur?

A

relaxation
activates guanylyl cyclase which increases cGMP
activating PKG which activates myosin phosphatase
myosin phosphatase promotes relaxation of the muscle

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25
Q

What stimulants can activate endothelial cells in unhealthy endothelium?

A

interleukin-1 (IL-1)
endotoxin (bacterial cell wall)
thrombin (platelets)

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26
Q

What can stimulants of unhealthy endothelium activate?

A

endothelin-1 (ET-1)

ROS

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27
Q

What does endothelin-1 (ET-1) do in VSMCs?

A

contraction

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28
Q

What can disturbed blood flow in unhealthy endothelium activate?

A 
ROS
ICAM-1
VCAM-1
IL-8
COX-2
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29
Q

What do ICAM-1 and VCAM-1 expression lead to? What effect does this have on the endothelium?

A

increased expression of adhesion molecules at the cell surface and shedding of the glycocalyx
increased monocyte, neutrophil and platelet interactions promoting transmigration across the artery wall and atherosclerosis

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30
Q

How does calcium signalling cause contraction of the VSMCs?

A

increased intracellular calcium forms a complex with calmodulin
this complex binds to myosin light chain kinases which phosphorylate myosin leading to activation and contraction

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31
Q

How does contracted VSMCs relax?

A

myosin phosphatase is constitutively active and works to dephosphorylate myosin

32
Q

What is the cells source of calcium?

A

calcium store in the sarcoplasmic reticulum

33
Q

How is low intracellular calcium normally maintained?

A

calcium-ATPase pumps on the plasma membrane and SR membrane

34
Q

What are the two routes VSMC contraction can occur?

A

GPCRs and calcium channels

35
Q

What can stimulate GPCRs?

A 
enodthelin A/B
TP (prostanoid)
AT1 (angiotensin 1)
histamine
NA
36
Q

How does activation of GPCRs lead to calcium release?

A

active GPCR activates IP3 which signals calcium channels on the SR to open increasing intracellular calcium levels

37
Q

What are the different types of calcium channels?

A 
voltage sensitive (L-type)
receptor operated (e.g. P2X)
TRP channels 
store operated (Ora1)
38
Q

What are the three mediators of VSMC relaxation?

A

cGMP
cAMP
potassium channels

39
Q

How does cGMP mediate VSMC relaxation?

A

activation of PKG

PKG acts on myosin phosphatase which dephosphorylates myosin leading to relaxation

40
Q

What mediated increased cGMP?

A

increased NO from endothelium which activates guanylyl cyclase

41
Q

How does cAMP mediate VSMC relaxation?

A

increased cAMP decreases calcium concentration

prevents myosin light chain kinase from working and no contraction to occur

42
Q

What mediates increased cAMP?

A

beta-agonists, adenosine and prostaglandins

bind to Gs proteins which increase cAMP through adenylyl cyclase activation

43
Q

How does potassium mediate VSMC relaxation?

A

potassium efflux from the cell leads to hyperpolarisation

this leads to decreased calcium preventing myosin light chain kinase from working and no contraction to occur

44
Q

What mediates increased open probability of the potassium channel?

A

beta-agonists via the beta-gamma G-protein

45
Q

Give two examples of potassium channels

A 
BK channels (large conductance)
SK channels (small conductance)
46
Q

What endothelial mediators lead to VSMC contraction?

A

prostanoids
endothelin-1
angiotensin II

47
Q

What is the function of nitric oxide (NO)?

A

an endothelial-derived vasodilator responsible for regulating blood pressure and regional blood flow

48
Q

What is dysregulation of NO linked to?

A

cardiovascular risk factors

49
Q

What impairs eNOS?

A

smoking
high glucose and insulin
oxLDL

50
Q

How does smoking affect NO dysregulation?

A

reduction in NO bioavailability
interferes with eNOS acetylation
loss of eNOS anchored to the membrane

51
Q

How does hyperglycaemia affect NO dysregulation?

A

reduced eNOS phosphorylation
reduced bioavailability in NO
may act via loss of coupling in the Akt pathway

52
Q

How does oxLDL affect NO dysregulation?

A

depletion cholesterol from caveolae causing loss of eNOS

displacement of ENOS from caveola through binding to CD36 scavenger receptors

53
Q

What does disturbed eNOS function lead to?

A

hypercholesterolaemia

54
Q

What does NO dysregulation lead to?

A

inability to regulate blood pressure and hypertension

55
Q

What risk factors are linked to ageing and disease?

A 
atherosclerosis
damage to glycocalyx
calcification
loss of elastin
decreased NO
increased blood pressure and hypertension
56
Q

What does atherosclerotic plaques cause?

A

increased separation of endothelium from VSMCs
loss of regulation of artery contractility
raised blood pressure
loss of elasticity - reinforcing loss of relaxation

57
Q

Damage to the glycocalyx is caused by?

A 
hyperglycaeia
hyperlipidaemia
smoking
sepsis
inflammation
58
Q

How are endothelial-derived Prostanoids produced?

A

increased intracellular calcium or ROS activate COX1/2 enzymes which convert arachidonic acid into prostanoids

59
Q

Give three examples of Prostanoid derivatives

A 
thromboxane A2 (TxA2)
prostaglandin E2 (PGE2)
prostaglandin I2 (PGI2)
60
Q

By what mechanism does Thromboxane A2 (TxA2) affect VSMCs?

A

thromboxane A2 binds to thromboxane receptor (TP) on VSMC plasma membrane
TP receptor couples to PLC activating and producing IP3 which signal calcium release from the SR
increased intracellular calcium leads to muscle contraction

61
Q

By what mechanism does Prostaglandin E2 (PGE2) affect VSMCs?

A

prostaglandin E2 binds to prostaglandin E2 receptors (EP1-4)
some activate adenylyl cyclase via Gs GPCRs which leads to a reduction in cAMP leading to muscle contraction
other inhibit adenylyl cyclase via Gi GPCRs which increases the cAMP levels, which activates of PKA
PKA activates myosin phosphatase leading to muscle relaxation

62
Q

What is the effect of PGE2 dependent on?

A

the relative expression of the EP receptor subtypes on VSMCs

63
Q

By what mechanism does Prostaglandin I2 (PGI2) affects VSMCs?

A

binds to IP receptors (IP-R) on VSMC plasma membranes
IP GPCR receptor couples to activation of adenylyl cyclase leading to an increase in cAMP which activates PKA
PKA activates myosin phosphatase leading to muscle relaxation

64
Q

What is the precursor of Endothelin-1 (ET-1)? What upregulates this precursor?

A

big endothelin

inflammatory or pathogenic

65
Q

What enzyme mediates the breakdown of big endothelin to endothelin-1

A

endothlin converting enzyme (ECE)

66
Q

By what mechanism does endothelin-1 act on VSMCS?

A

ET-1 act on either ET alpha or beta (ETA/ETB) GPCR-Gq receptors which couples with PLC leading to activation and production of IP3
acting of calcium channels in SR membranes to increase intracellular calcium leading to muscle contraction

67
Q

By what mechanism does endothelin-1 acts on endothelial cells?

A

negative feedback
ET-1 acts on ETB receptors on endothelial cell plasma membrane which increases intracellular calcium causing production of NO from arginine via eNOS
NO inhibits ECE down-regulating the production of endothelin-1

68
Q

How is Angiotensin II produced?

A

ACE enzyme converts angiotensin I into angiotensin II

69
Q

Where are ACE enzymes predominantly expressed?

A

expressed at the membrane of pulmonary and renal vasculature endothelial cells

70
Q

By what mechanism does Angiotensin II act on VSMCs?

A

angiotensin II binds to AT1 receptors on VSMC plasma membranes which can activate PLC leading to increased IP3 which activates calcium channels on the SR membrane
increased intracellular calcium leads to muscle contraction
AT1 receptors can also activate MAPK signalling

71
Q

What does MAPK singalling lead to in VSMCs?

A

makes VSMCs more contractile in their responses

more persistent changes in VSMC responses

72
Q

What effect does smoking have on vascular function?

A

damages glycocalyx on endothelin which increases adhesion, activation of endothelin and initiation of atherosclerosis
reduces the bioavailability of NO and stops eNOS attachment to the membrane

73
Q

What effect does hyperlipidaemia (high oxLDL) have on vascular function?

A

depletion of cholesterol from endothelial caveoli, reducing the function of eNOS
fatty plaque build up which separate the connections between endothelial cells and VSMCs
increased endothelin production leading to increased VSMC contraction

74
Q

What effect does hyperglycaemia have on vascular function?

A

excessive insulin dampens the Akt pathway on eNOS activity
increased damaged to the glycocalyx
increased endothelin production from endothelial cells leading to increased VSMC contraction

75
Q

What effect does ageing have on vascular function?

A

loss of elastin/stretch

loss of compliance if arteries

76
Q

What effect does infection have on vascular function?

A

pathogens and inflammatory/immune response activate endothelium
recreation of leukocytes to the artery wall weaken atherosclerotic plaques
these stimuli generally activate pathways leading to increased VSMC contraction

CDL301 (14 decks)

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