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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
What stimulants can activate endothelial cells in unhealthy endothelium?
interleukin-1 (IL-1) endotoxin (bacterial cell wall) thrombin (platelets)
26
What can stimulants of unhealthy endothelium activate?
endothelin-1 (ET-1) | ROS
27
What does endothelin-1 (ET-1) do in VSMCs?
contraction
28
What can disturbed blood flow in unhealthy endothelium activate?
``` ROS ICAM-1 VCAM-1 IL-8 COX-2 ```
29
What do ICAM-1 and VCAM-1 expression lead to? What effect does this have on the endothelium?
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
30
How does calcium signalling cause contraction of the VSMCs?
increased intracellular calcium forms a complex with calmodulin this complex binds to myosin light chain kinases which phosphorylate myosin leading to activation and contraction
31
How does contracted VSMCs relax?
myosin phosphatase is constitutively active and works to dephosphorylate myosin
32
What is the cells source of calcium?
calcium store in the sarcoplasmic reticulum
33
How is low intracellular calcium normally maintained?
calcium-ATPase pumps on the plasma membrane and SR membrane
34
What are the two routes VSMC contraction can occur?
GPCRs and calcium channels
35
What can stimulate GPCRs?
``` enodthelin A/B TP (prostanoid) AT1 (angiotensin 1) histamine NA ```
36
How does activation of GPCRs lead to calcium release?
active GPCR activates IP3 which signals calcium channels on the SR to open increasing intracellular calcium levels
37
What are the different types of calcium channels?
``` voltage sensitive (L-type) receptor operated (e.g. P2X) TRP channels store operated (Ora1) ```
38
What are the three mediators of VSMC relaxation?
cGMP cAMP potassium channels
39
How does cGMP mediate VSMC relaxation?
activation of PKG | PKG acts on myosin phosphatase which dephosphorylates myosin leading to relaxation
40
What mediated increased cGMP?
increased NO from endothelium which activates guanylyl cyclase
41
How does cAMP mediate VSMC relaxation?
increased cAMP decreases calcium concentration | prevents myosin light chain kinase from working and no contraction to occur
42
What mediates increased cAMP?
beta-agonists, adenosine and prostaglandins | bind to Gs proteins which increase cAMP through adenylyl cyclase activation
43
How does potassium mediate VSMC relaxation?
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
What mediates increased open probability of the potassium channel?
beta-agonists via the beta-gamma G-protein
45
Give two examples of potassium channels
``` BK channels (large conductance) SK channels (small conductance) ```
46
What endothelial mediators lead to VSMC contraction?
prostanoids endothelin-1 angiotensin II
47
What is the function of nitric oxide (NO)?
an endothelial-derived vasodilator responsible for regulating blood pressure and regional blood flow
48
What is dysregulation of NO linked to?
cardiovascular risk factors
49
What impairs eNOS?
smoking high glucose and insulin oxLDL
50
How does smoking affect NO dysregulation?
reduction in NO bioavailability interferes with eNOS acetylation loss of eNOS anchored to the membrane
51
How does hyperglycaemia affect NO dysregulation?
reduced eNOS phosphorylation reduced bioavailability in NO may act via loss of coupling in the Akt pathway
52
How does oxLDL affect NO dysregulation?
depletion cholesterol from caveolae causing loss of eNOS | displacement of ENOS from caveola through binding to CD36 scavenger receptors
53
What does disturbed eNOS function lead to?
hypercholesterolaemia
54
What does NO dysregulation lead to?
inability to regulate blood pressure and hypertension
55
What risk factors are linked to ageing and disease?
``` atherosclerosis damage to glycocalyx calcification loss of elastin decreased NO increased blood pressure and hypertension ```
56
What does atherosclerotic plaques cause?
increased separation of endothelium from VSMCs loss of regulation of artery contractility raised blood pressure loss of elasticity - reinforcing loss of relaxation
57
Damage to the glycocalyx is caused by?
``` hyperglycaeia hyperlipidaemia smoking sepsis inflammation ```
58
How are endothelial-derived Prostanoids produced?
increased intracellular calcium or ROS activate COX1/2 enzymes which convert arachidonic acid into prostanoids
59
Give three examples of Prostanoid derivatives
``` thromboxane A2 (TxA2) prostaglandin E2 (PGE2) prostaglandin I2 (PGI2) ```
60
By what mechanism does Thromboxane A2 (TxA2) affect VSMCs?
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
By what mechanism does Prostaglandin E2 (PGE2) affect VSMCs?
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
What is the effect of PGE2 dependent on?
the relative expression of the EP receptor subtypes on VSMCs
63
By what mechanism does Prostaglandin I2 (PGI2) affects VSMCs?
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
What is the precursor of Endothelin-1 (ET-1)? What upregulates this precursor?
big endothelin | inflammatory or pathogenic
65
What enzyme mediates the breakdown of big endothelin to endothelin-1
endothlin converting enzyme (ECE)
66
By what mechanism does endothelin-1 act on VSMCS?
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
By what mechanism does endothelin-1 acts on endothelial cells?
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
How is Angiotensin II produced?
ACE enzyme converts angiotensin I into angiotensin II
69
Where are ACE enzymes predominantly expressed?
expressed at the membrane of pulmonary and renal vasculature endothelial cells
70
By what mechanism does Angiotensin II act on VSMCs?
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
What does MAPK singalling lead to in VSMCs?
makes VSMCs more contractile in their responses | more persistent changes in VSMC responses
72
What effect does smoking have on vascular function?
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
What effect does hyperlipidaemia (high oxLDL) have on vascular function?
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
What effect does hyperglycaemia have on vascular function?
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
What effect does ageing have on vascular function?
loss of elastin/stretch | loss of compliance if arteries
76
What effect does infection have on vascular function?
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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