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Fetus > Molecular mechanisms of labour > Flashcards

Molecular mechanisms of labour Flashcards

1
Q

What are the potential mechanisms of the onset of labour

A

Binary switch
Placental clock- CRH/ACTH/HPA axis
Fetal derived signal
Infection

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2
Q

Describe the placental clock mechanism of labour

A

Increased placental corticotrophin releasing hormone towards term stimulates fetal pituitary to release ACTH
ACTH increases fetal adrenal DHEA
DHEA is major oestrogenic precursor
Oestrogens increase myometrial gap junctions which facilitate regular coordinated uterine contractions

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3
Q

Why is the placental clock mechanism not the sole mechanism for labour

A

Anencephalic pregnancies are post term but deliver spontaneously
Lack part of the pathway for placental clock theory

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4
Q

Describe the fetal derived signal mechanism for labour

A

ACTH may be related to fetal surfactant proteins
Increased surfactant secretion at term activates amniotic fluid derived macrophages
AF macrophages migrate to uterine wall and activate inflammatory gene expression

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5
Q

What chemicals are required for onset of labour

A

Prostaglandins
Cytokines
Chemoattractant cytokines

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6
Q

What happens in preparation for labour

A

Myocyte depolarisation
Elevation of intracellular Ca2+
Increased expression of gap junction proteins
Functional progesterone withdrawal

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7
Q

What is functional progesterone withdrawal

A

there is no decline in plasma progesterone levels prior to parturition but progesterone receptor agonists induce termination
Something blocks progesterone at term
Possibly: different isoforms of receptor becoming dominant, estrogen activity becoming dominant, local metabolism to inactive form

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8
Q

What are the 3 layers of smooth muscle in the uterus

A

Inner circular layer- underlies endometrium, junctional zone, responsive to oestrogen
Interlocking middle layer
Outer longitudinal layer

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9
Q

Describe the spatial expression patterns of protein in the myometrium

A

Different levels of protein expression between each region
Possibly reflects function
Proteins include gap junction proteins, NFkB, RNA splicing proteins

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10
Q

Describe myometrial quiescence

A

Balance between contraction and relaxation
Balance between proquiescent and contractile molecules
Not just absence of contraction

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11
Q

What are the proquiescent molecules

A

Progesterone, Gas, CRH, cAMP, PKA, PKC, cGMP, NO

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12
Q

What are the contractile molecules

A

Oestrogen, CRH, Gaq, oxytocin, PGE2, PGF2a, Ca2+, IP3

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13
Q

Describe how signalling cascades influence myometrial contraction

A 
L and T type Ca2+ channels
Agonists cause calcium spikes
Calcium modulated by calmodulin
Chain reaction resulting in activation of actomyosin ATPase
Causes myocyte contraction
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14
Q

What are the 3 Ga subunits

A

Gas
Gai
Gaq

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15
Q

Describe Gas signalling

A

Positive signalling
cAMP second messenger
B2 agonists eg. PGE2 act through EP2 receptor
Cause uterine relaxation and quiescence

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16
Q

Describe Gai signalling

A 
Negative signalling
Prevents cAMP production
Involves alpha andrenergic agonists eg. ergometrine
Opiod receptors
PGE2 acting via EP1 and EP3 receptors
Causes uterine contraction
Can be targeted by misoprostol
17
Q

Describe Gaq signalling

A 
Positive signalling
IP3 + DAG second messengers
Oxytocin receptor
PGF2 acting via FP2a receptor
Causes uterine contraction
Targeted by carboprost
18
Q

What are the 3 signalling pathways involved in myometrial quiescence

A

Gas receptors increasing cAMP
Calcium regulated potassium channels causing myocyte hyperpolarisation
PKA phosphorylation of intracellular proteins activating acto-myosin ATPase

19
Q

What are B2 agonists

A

Eg. Ritodrine, salbutamol
Respond to adrenaline and noradrenaline
Increase cAMP, promote smooth muscle relaxation + quiescence
Promotes myocyte hyperpolarisation and open K+ channels
Tocolytic activity

20
Q

What is Gas

A

GTP-binding protein
Elevates cAMP and PKA activity
Present during pregnancy, downregulated during labour
Loss of Gas may cause contractions

21
Q

Describe how inflammation disturbs the Gas promoter

A

Normal: No TNF, limited amount of CBP, acetylated histones, open chromatin, expression of Gas
Inflammation: TNF, elevated HDAC1, reduced CBP, reduced histone acetylation, closed chromatin, gene repression

22
Q

What regulates inflammatory factors

A

NFkB

23
Q

How does TSA inhibit myometrial contraction

A

Inhibits HDACs
HDACs remove acetylation so close chromatin
TSA prevents Gas being turned off
High levels of TNF can overcome repression

24
Q

Describe canonical activation of NFkB

A

Involves TNFa, IL18, LPS
IkBa on NFkB targeted for degradation by 26s proteasome
NFkB binds promoter to increase IkBa expression

25
Q

Describe non-canonical activation of NFkB

A

Involves BAFF, CD40, LPS
P100 CTD degradation by 26s proteasome
Promotes unknown gene expression

26
Q

Describe hypoxic activation of NFkB

A

Promotes HIF expression

27
Q

What proinflammatory factors are associated with labour

A

COX2, IL1B, IL6, IL8, TNF

Regulated by NFkB

28
Q

Describe gene analysis experiment during inflammation

A

TNF stimulation- 13300 enriched regions, 46% intronic

Unstimulated- 11110 regions, 54% intronic

29
Q

What are the 3 stages of parturition

A 
Cervical dilation/remodelling
Fetal expulsion (myometrial contraction)
Placental delivery
30
Q

What is involved in the transition from quiescence to contractile

A

Inflammation
Differential gene expression
Elevated Ca2+

31
Q

Describe the role of Ca2+ in contractility

A

Calcium regulated contraction pathways
Extracellular sources target voltage gated Ca2+ channels
Intracellular stores act on channels on sarcoplasmic reticulum

32
Q

What treatment for premature contractions targets Ca2+ channels

A

Nifedipine
Ca2+ channel blocker
Normally treatment for high blood pressure. Relaxes smooth muscle, increase luminal volume

33
Q

Describe the role of oxytocin in contractions

A

Increased receptor numbers at term in fundal myometrium
Cervical stimulation/ myometrial stretch increases oxytocin secretion from paraventricular nuclei of hypothalamus
Positive feedback mechanism = ferguson reflex

34
Q

What oxytocin analogue is used to induce labour

A

Syntocinon

35
Q

Describe an oxytocin receptor agonist

A

Atosiban
Can inhibit premature myometrial contractions
Specific to oxytocin receptors
Doesn’t revert to full quiescence

36
Q

What signals regulate myometrial quiescence

A 
G-protein signalling particularly Gas
B2 adrenergic receptor activation facilitating K+ extrusion
Myocyte hyperpolarisation
Nitric oxide
hCG
PGER1 + PGER3

Fetus (18 decks)

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