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CDL301 > Physiology of vasculature > Flashcards

Physiology of vasculature Flashcards

1
Q

How do we regulate blood supply

A

Vessel relaxation- widening, increases supply

vessel contraction- narrowing, decreases blood supply

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2
Q

Regulating blood supply for organs

A

Exercise- increases supply to muscles, lungs and heart
digestion- increases supply to GI tract
Thermoregulation 1. vasoconstriction and 2. vasodilation- heat loss across the epidermis
capillaries dilate further away from the body to get heat loss

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3
Q

Why do we need to understand the vascular physiology?

A

arterial contraction/ relaxation results in changes in blood pressure
artery wall dysfunction underlies diseases
- atherosclerosis- initiated by dysfunctional blood vessels
- hypertension- high blood pressure due to vessel contraction

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4
Q

The vasculature of blood vessels

A

vein- adentia, smooth muscle, endothelium and then lumen most inside
Artery- the same- strong as they supply with blood pumping away from the heart, contract and relax
arterioles- come off arteries
Smaller muscular arteries and arterioles are the main resistance vessels
vein= resupply blood back to heart

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5
Q

Why is contraction and relaxation tightly controlled?

A

to regulate blood supply to organs and determine blood pressure

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6
Q

Structure of the artery wall

A

Outside to inside
tunica externa- strong fibrous tissue to maintain blood vessel shape
elasticity
tunica media- contains smooth muscle, elastin, collagen matrix
tunica intima- connective tissue
endothelium- thin layer of cells in direct contact with the blood

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7
Q

What does smooth muscle do?

A

Contracts and relaxes to determine the size of the artery .

mediators released from endothelium and sympathetic nerves

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8
Q

Proximity of endothelium to vascular smooth muscle cells

A

Smooth muscle= thicker

neurones are deeper in the artery to act directly on smooth muscles

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9
Q

Intracellular communication between endothelium and VSMCs

A

release factors that act directly

direct contact between via gap junctions

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10
Q

Gap junctions

A

between smooth muscle cells, physically coupling

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

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11
Q

What is the endothelium?

A

Line every blood vessel
target organ surface covers > 1 football pitch
Health endothelium= healthy CV system
Unhealthy or activated Endothelium= disease- critical in the first changes that take place to cause disease (dysregulating BO and initiating events underlying atherosclerosis and thrombosis)

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12
Q

Non pathological conditions of the endothelium

A

Glycocalyx

  • intact in nonactivation endothelium
  • anti-coagulant- form continuous coating
  • lubricant that stops circulating cells from binding to adhesion molecules on endothelial surfaces
  • consists of carbohydrates and sugar chains protruding from the apical surface of the endothelium
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13
Q

What causes activated/ dysfunctional endothelium?

A
  • injury, injection or inflammation
  • oxLDL (lipid)
  • disturbed blood flow (oscillatory shear stress)
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14
Q

What happens when an endothelium is activated/ dysfunctional? / branched arteries with disturbed flow?

A
  1. Adhesion molecules bind to glycans on circulating blood cells including monocytes, neutrophils and platelets
  2. Glycocalyx shredding
  3. monocyte enters artery wall
  4. initiates/ progresses atherosclerosis
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15
Q

Where does activated endothelium take place?

A

At sites of disturbed blood flow
branches and bends in the artery
straight vessels- blood flow exerts an event of shear stress force against the well
branched= disturbed

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16
Q

Endothelial cell signalling in a healthy endothelium

A

stimulated by neurotransmitters such as Ach, histamine, 5-HT and bradykinin

  • bind to various receptors to mediate an increase in IC ca
  • activate eNOS to convert argine to NO and citrulline
  • High shear stress which occurs in straight arteries- increase NO
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17
Q

Endothelial cell signalling in an unhealthy or activated endothelium

A
  • stimuli activates EC- interleukin-1, endotoxin ( bacteria in cell wall) and thombin (from platelets)
  • disturbed flow act on ROS, ICAM-1, VCAM-1(adhesion molecules),il3 and cox2 to increase
  • increased adhesion molecule expression and shredding of glycocylax
  • leads to increased monocyte, neutrophil and platelet interactions
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18
Q

ET-1

A

released from cells and act adjacent to VSMC

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19
Q

What are VSMC controlled by?

A

intracellular Ca levels- key regulator in contractibility

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20
Q

What happens in resting or relaxed smooth muscles?

A

intracellular Ca is maintained low by Ca ATPase pumps in plasma membrane and SR

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21
Q

What do smooth muscles need to be active?

A

Myosin needs P

Phosphate

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22
Q

How does VSMC Contraction occur?

A

Second messengers can increase ca intracellular levels by activating release from SR stores

This leads to binding by calmodulin to form a complex (Ca-CaM)

  • This activates myosin light chain kinase which phosphorylates myosin cause activation (MLCK)+P
  • actin cross bridge cycle starts= contraction
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23
Q

How is smooth muscle distinct from skeletal muscle?

A

Smooth muscle myosin mist be phosphorylated to be active

Myosin phosphatase is constitutively active so cell tends to relax in absence of stimuli

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24
Q

What couples to IP3 and what does it do?

A

Second messengers couple to IP3 and cause intracellular Ca to be released and then activation of the myosin phosphorylation contraction pathway

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25
Q

GPCRS

A 
endothelium A/B 
TP (prostanoid)
AT1 (angiotensin)
histamine
noradrenaline (a-AR)
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26
Q

Calcium channels

A 
Voltage sensitive (L type)
receptor operated (eg. P2X)
TRP channels 
store operated (Ora1)
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27
Q

What activates these pathways?

A

GPCR activate these pathways.
Different types of Ca channels- voltage, storage, Receptor
Different types of pathways that act to increase intracellular ca

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28
Q

vascular smooth muscle cell relaxation pathways

A
  1. Nitric oxide- from endothelium- increase cGMP
  2. Gs coupled
  3. K channel
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29
Q

What is the nitric oxide pathway?

A

Nitric oxide to GC(guanylyl cyclase) which activates cGMP and the activates PKG which activating PDE

  • Decreases Ca
  • increases myosin phosphatase
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30
Q

3 key mediators of relaxation

A

cGMP
cAMP
K channels
All block Ca

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31
Q

Gs coupled pathway?

A

B agonists, adenosin, prostaglandins

Activates AC which activates cAMP to increase PDE and decrease Ca which causes relaxation

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32
Q

K channels

A

BK channel, SK channels, B agonists

K efflux from K channel causes hyperpolarisation which then decreases IC Ca

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33
Q

What does PDE do?

A

hydrolyse 2nd messengers, reduce amount present and reduce relaxation of response

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34
Q

What does the endothelium contribute to controlling vascular smooth muscle contraction?

A

source of many mediators that actively control smooth muscle cell contraction

35
Q

What is the top of EC in contact with and what does it respond to?

A 
in contact with blood (apical surface)
responds to:
1. circulating hormones 
2. thrombin from platelets- injury 
3. cytokines and infectious stimuli- inflammation/ immune response 
4. shear stress
36
Q

What results does the EC response have on intracellular signalling in the endothelial cell?

A
  1. some via rise in intracellular Ca
  2. signalling is independent of ca (some)
  3. gap junctions between endothelium and VSMC allow electrical coupling- level of endothelial hyperpolarisation in resistance vessels
37
Q

4 key endothelial mediators

A

Nitric oxide pathway
proteinoids
endothelin
angiotensin II

38
Q

Mechanism of nitric oxdide derived vasodilator

A

1980- endothelial derived relaxing factor
NO regulates blood pressure and regional blood flow

vasodilators act to increase NO production
GPCR couple and cause increase in IC ca calmodulin-n responsible for NOS
- NO activates GC which increases cGMP and causes relaxation

39
Q

Where is NO produced?

A

in the epithelium in response to increase in Ca IC

released from endothelial cells after production- freely permeable and diffuses to act on VSMC

40
Q

What is an additional regulatory mechanism of NO?

A

regulatory at the P of specific residues of ENOS
regulate sensitivity to calcium calmodulin
shear stress regulates ENOS

41
Q

How does NO affect the VSMC

A

NO relaxes smooth muscle by acting on guanylyl cyclase to increase cGMP
increase cGMP activates PKG which activates myosin on phosphatase
leading to relaxation
cGMP also decreases IC Ca directly

42
Q

how is nitric oxide dysregulated?

A

By the same factors as CVD

  • smoking= reduces NO bioavailability
  • high glucose and insulin= less ENOS P
  • ocLDL- depletes cholesterol from caveolae- loss of ENOS
43
Q

What happens if you reduce the amount of NO or ENOS?

A

Raised blood pressure as more contraction

44
Q

How does oxLDL affect Blood pressure?

A

displaces eNOS from caveolae
hypercholesterolaemia
means that NO production is dysregulated leading to loss of ability to regulate blood pressure- increased hypertension

45
Q

ENOS with caveoli

A

ENOS is acetylated and complexes with the Golgi and caveolae
caveolae structures contain clusters of eNOS enzymes
result in NO being produced
act rapidly on VSMC

46
Q

Mechanism of action of Endothelial derived prostanoids?

A

prostanoids- produced in endothelium in response to increase Ca or ROS

  • activates cyclo-oxygenase 1/2 enzymes to convert arachidonic acid to PGH2
  • PGH2 - converted to number of prostanoid derivatives
47
Q

Prostanoid derivatives

A
  • Thromboxane (A2)
  • Prostagladin Es (PGE)
  • PGI1
48
Q

What does Thromboxane A2 do?

A

released from EC to act on TP- TPGPCR to PLC activation and IP3 production
releases CA
muscle contracts

49
Q

Prostagladin E2 (PGE2)

A

Acts on PGE2 receptors and some EP receptors
activate GC
increase cGMP= relaxation, decrease cGMP= contraction

50
Q

PGH2

A

acts on IP receptor on VSMC
IPGPCR recptors couple to activate adenylyl cyclase to increase cAMP- relaxation
vasodilator

51
Q

What activates PKA

A

cAMP - then activates myosin phosphatase to mediate relaxation

52
Q

endothelial derived endothelium ET-1

A

Precursor of ET-1 is big endothelium which is regulated by a variety of stimuli (inflammatory or pathogenesis)

  • endothelium enzyme cleaves to ET-1
  • ER-1 released from EC to act on VMCS at both ETA and B GPCR Gp receptors
  • this couples to contraction response via PLC and IP3
53
Q

What is the negative feedback mechanism of of ET-1

A

ET-1 acts back on EC via ETB receptors to block ECE activity
and increases NO
oppose contraction

54
Q

What does the endothelium express? Why is this important?

A

only expresses ETB not a

Of interest therapeutically as we may wish to specifically block ETA receptors NOT etB

55
Q

What is ACE?

A

Predominantly expressed on EC of pulmonary and renal vasculature converts circulating angiotensin I

56
Q

What is AGII?

A

acts on ATi R on VSMC

57
Q

What is AT1

A

activates MAPK pathway in VSMC leading to persistent changes in signalling to make more contractible in their response
long term effects on smooth muscle

58
Q

Ageing and disease- what goes wrong?

A 
Atherosclerosis 
damage 
calcification 
loss of elastin 
decrease NO- diet, smoking hypoxia
59
Q

What happens during atherosclerosis?

A

Build up of plaque in arteries
means the endothelium is more separate from VSMC
loss of coupling between them
- loss of contractibility of artery
- results in raised blood pressure
- more strain on arteries
- loss of elasticity and can reinforce loss of function

60
Q

What causes damage to the glycocalyx?

A
  • hyperglycaemia- excessive insulin dampens akt effect on eNOS
  • hyperlipidaemia- deplete cholesterol from endothelial caveoli, reduce function of eNOS + atherosclerosis
  • smoking- reduceds NO bioavailability
  • sepsis and inflammation- activates leukocytes to artery wall- weakens atherosclerotic plaque
61
Q

What are diseases which target the vasculature?

A
  • Hypertension
  • HF
  • angina
  • pulmonary hypertension
  • Raynaud syndrome
62
Q

What is hypertension?

A

High blood pressure
affects 30% of people in England
increase risk of MI or stroke

63
Q

Symptoms of hypertension?

A

breathlessness, fatigue, fluid retention as CO is not adequate to meet metabolic demands

64
Q

Causes of hypertension

A

most commonly secondary to atherosclerosis

65
Q

risk factors to damage to vascular function

A

Smoking- damage glycocalyx, reduce NO bioavailability
hyperlipidaemia- reduced eNOS, fatty plaques
hyperglycaemia- insulin dampens akt effect on eNOS, damage glycocalyx and increased endothelin production (vsmc contraction)
ageing- loss of elastin
infection- leukocytes recruited
high sodium- reduced NO

66
Q

What happens when there is loss of vasodilation?

A

Hypertension

67
Q

What is heart failure?

A

Inadequate CO to meet metabolic demands

disease of heart MI or atherosclerosis

68
Q

What is angina?

A

O2 supply to heart is insufficient upon exertion
chest pains
due to coronary artery disease

69
Q

What is pulmonary hypertension?

A

Narrowing of pulmonary arteries
increase pressure on right side
life expectancy 1-3 years from diagnosis

70
Q

What is Reynard’s syndrome?

A

Inappropriate vasoconstriction of smaller arteries/ arterioles
white/ blue fingers to red
severe cases- ulceration and gangrene

71
Q

What are primary and secondary Raynaud’s?

A
  1. hereditary or idiopathic

2. connective tissue disorder, obstruction, drug side effects

72
Q

Treatment for Raynaud’s?

A

stop smoking, avoid cold, vasodilator therapies

73
Q

What is the drug target for these diseases?

A

Vasculature
most therapies= vasodilators requiring relaxation of VSMC
Therapies act on 4 endothelial mediator (NO, ET-1, prostanoids, angiotensin II)

74
Q

Endothelial derived vasodilators- nitric oxide donors

A

nitroglercine= converts into NO by mitochondrial aldehyde dehydrogenase- spray
sodium nitroprusside= emergency hypertension- injection
inhaled NO= pulmonary hypertension (server)

75
Q

Prostamoid vasodilators

A 
Iloprost= PG1/2- pulmonary hypertension or Raynaud's - inhaled or IV
Epoprostenol= IP receptor agonist, same uses in pulmonary hypertension
Corticosteroids= supresses formation of prostagldins, prevent shock
76
Q

ET-1 vasodilators

A

ETa/b Inhibition= bosentan- prevent hypertension, phase 3 clinical trial, ischaemic optic neuropathy from glaucoma
ECE inhibitor= phophoramidon, experimental tool

77
Q

Angiotensin II vasodilators

A

ACE inhibitors= hypertension, HF and after MI
types:
- captopril- side effects: hypotension, cough, proteinuria, weird taste
- enalapril- require conversion to active metabolite, longer acting

AT1 receptor antagonists
- blood pressure reduction
sartans- lostartan, valsartan
- inhibit production of angiotensins at renin-angiotensin-aldosterone system

78
Q

Directly acting therapies for VSMC? (4)

A
  1. nifedipine= hypertension, raynauds, angina
  2. verapramil= hypertension, HF
  3. diltrazem= hypertension, angina
  4. minoxidil= anti-hypertensive (most commonly used to treat hairloss)
79
Q

What is a PDE inhibitor?

A

sildenafil= Viagra
treats pulmonary hypertension
*SHOULD NEVER BE TAKEN WITH NO

80
Q

What are the different types of hypertension treatments

A

sodium nitropusside- NO donor
ace inhibitor- Angiotensin II
Sartans AT1 receptor on VSMC
Nifedipine, verapamil and dilitiazem- Ca channel blockers
Minoxidil, diaxoxide- K channel activators in VSMC

81
Q

Different types of HF treatments?

A

ACE inhibitiors- Angiotensin II blocker

verapamil- block Ca channel in VSMC

82
Q

What are the treatments for angina?

A

Nitroglycerine- NO donor
diltiazem- Block Ca channels in VSMC
Nicorandil- K channel activator and NO donor

83
Q

What are the treatments for hypertension?

A

Inhaled NO- No on vsmc
Iloprost- prostacyclin, increase cAMP in VSMC
Bosentan- ETa/b antagonist- blocks IP3 mediates Ca release
Sildenafil (Viagra) - phosphodiesterase inhibitor, stops cAMP and cGMP hydrolysis

CDL301 (7 decks)

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