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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
What is blood flow like at branches/bends in vessels?
Blood flow becomes disturbed
26
Where do fatty plaques/activated endothelium mostly occur and why?
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
27
What signalling occurs within healthy endothelial cells?
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
28
What does NO released from endothelial cells do to VSMCs?
Causes relaxation
29
What factor does high shear stress increase in endothelial cells?
NO
30
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?
Interleukin-1 - proinflammatory cytokine Endotoxin - bacterial cell wall Thrombin - from platelets Disturbed blood flow
31
What do IL1, endotoxin, thrombin and disturbed blood flow all lead to an increase in?
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
32
On which side are factors secreted from endothelial cells to act on VSMC's?
Basolateral surface (into arterial wall)
33
How is Ca maintained in a resting VSMC?
Intracellular Ca maintained low by Ca ATPase pumps in plasma membrane or sarcoplasmic reticulum
34
What is the main way to cause an increase in Ca in VSMCs?
``` 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
What is the alternative way to cause an increase in Ca in VSMCs?
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
What are the two differences between smooth muscle and skeletal muscle?
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
What are the two pathways that lead to VSMC contraction?
Increased IP3 production | Increased intracellular Ca
38
What are the 5 GPCRs involved in VSMC contraction?
``` Endothelin A/B TP (prostanoid) AT1 (angiotensin) Histamine Noradrenaline (alpha-adrenergic) ```
39
What are the 4 Ca channels involved in VSMC contraction?
``` Voltage sensitive (L-type) Receptor operated (P2X) TRP channels Store operated (Ora1) ```
40
What 3 signalling molecules are involved in VSMC relaxation?
cGMP cAMP Activation of K channels
41
How does increased cGMP lead to VSMC relaxation?
Produced by guanylyl cyclase Reduced intracellular Ca Activate PKG --> activate myosin phosphatase --> more inactive myosin Hydrolysed by phosphodiesterase’s
42
How does increased cAMP lead to VSMC relaxation?
Produced by adenylyl cyclase | Reduced intracellular Ca Hydrolysed by phosphodiesterase’s
43
How does activation of K channels lead to VSMC relaxation?
K efflux causes hyperpolarisation | Reduced intracellular calcium
44
What are 3 K channels involved in VSMC relaxation?
``` BK channels (large conductance) SK channels (small conductance) Beta-agonists (via bg G-protein) ```
45
How does NO also play a role in VSMC relaxation?
Released from endothelium | Activates guanylyl cyclase
46
How do Gs coupled receptors also play a role in VSMC relaxation?
``` Activates adenylyl cyclase E.g. - Beta-agonists - Adenosine - Prostaglandins ```
47
Overall what 5 things does the apical side of the endothelium respond to?
``` 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
Overall what 4 mediators regulate VSMCs?
Nitric oxide Prostanoids Endothelin Angiotensin II
49
When is NO produced?
Produced by endothelium in response to a rise in Ca
50
What does NO activate?
Freely permeable and diffuses to act on the VSMCs | Activates guanylyl cyclase --> cGMP --> PKG --> myosin phosphatase --> VSMC relaxation
51
What does NO regulate?
Blood pressure and regional blood flow
52
What increases NO production?
Many vasodilators (e.g. ACh)
53
What regulates eNOS?
Shear stress regulates eNOS in resistance vessels via Akt | Phosphorylation of specific residues on eNOS regulates its sensitivity to calcium-calmodulin
54
What does cGMP directly decrease?
Intracellular Ca
55
What are caveoli?
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
What does eNOS form complexes with?
eNOS is acetylated and complexes with Golgi and caveolae
57
What 3 things is eNOS impaired by?
Smoking High glucose and insulin oxLDL
58
How does smoking affect eNOS?
Interferes with eNOS acetylation --> loss of eNOS anchored to membrane Reduces NO bioavailability
59
How does high glucose and insulin affect eNOS?
Reduces eNOS phosphorylation | Reduces NO bioavailability
60
How does oxLDL affect eNOS?
Depletes cholesterol from caveolae --> loss/displacement of eNOS Disturbs eNOS function --> NO production dysregulated
61
When are prostanoids produced?
By endothelium in response to a rise in Ca or ROS
62
What do prostanoids activate
Activate COX 1/2 enzymes | Convert arachidonic acid to PGH2
63
What is PGH2 converted into?
Converted into prostanoid derivatives depending on the enzymes present - Thromboxane A2 - Prostaglandin E2 - Prostaglandin I2
64
PGH2 --> thromboxane A2 overview
Act on prostanoid thromboxane receptor (TP) | TP GPCR receptor --> PLC activation and IP3 production --> intracellular Ca release --> muscle contraction
65
PGH2 --> prostaglandin E2 overview
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
PGH2 --> prostaglandin I2 overview
Acts on the IP receptor | IP GPCR receptor --> adenylyl cyclase activation --> increased cAMP --> relaxation
67
Endothelial cells produce ET-1 when exposed to?
``` IL-1 Thrombin Glucose Ox-LDL Insulin Angiotensin II ```
68
How do endothelial cells produce endothelin?
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
What is the ET-1 negative feedback mechanism?
ET-1 acts back on endothelium via ETB receptors to block ECE activity This increases Ca inside endothelium --> increases NO --> opposes VSMC contraction
70
How is the ET-1 negative feedback mechanism of interest therapeutically?
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
How is angiotensin II produced?
By the action of ACE on endothelial cells
72
Where is ACE predominantly expressed?
On endothelial cells of pulmonary and renal vasculature
73
What does ACE convert?
Converts circulating angiotensin --> angiotensin II --> AT1 receptors --> PLC activation and IP3 production --> intracellular Ca --> contraction
74
What else do AT1 receptors also activate?
MAPK pathways in VSMC --> more persistent changes in signaling --> VSMCs more contractile
75
How does ageing affect endothelial cells?
Cause changes where endothelial cells no longer able to regulate the VSMCs All lead to increased blood pressure
76
What 5 changes can ageing cause which all lead to an increase in blood pressure?
``` Atherosclerosis Damage to glycocalyx Calcification Loss of elastin Decrease in NO ```
77
What is atherosclerosis?
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
What is damage to the glycocalyx caused by?
Hyperglycaemia Hyperlipidaemia Smoking Sepsis and inflammation
79
What is calcification?
Arteries become stiffer – less able to contract and relax
80
What causes a decrease in NO?
Diet Smoking Hypoxia

Personalised Medicine - Cardiovascular (11 decks)

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