molecular mechanisms of labour Flashcards
what is the muscle structure of the uterus?
myometrium -> 3 major layers of smooth muscle = inner circular layer, interlocking middle layer, outer longitudinal layer
what are the 3 gross regions of the uterus?
fundal region = super segment, to part, contractions emanate here
lower segment = develops during pregnancy, little contraction
cervix = closed during pregnancy, softens for labour
what are the spatial expression patterns of proteins in the myometrium?
different levels of protein expression between each region - high levels seen in the fundal region than lower segment
lower expression during labour than pregnancy
how does spatial protein expression regulate myometrial function/quiescence?
a balanced between contraction and relaxation
what are some pro-quiescent molecules?
progesterone GalphaS CRH cAMP PGE2 PKA
what are some contractile-associated molecules?
oestrogen CRH oxytocin PGE2 PGF2alpha calcium
what is the timeline to birth?
0wks/conception ->24wks = non-viable
24wks ->32wks = extremely premature
32wks->37wks = preterm
37wks -> 42 wks = term
what is the threshold of viability?
23-25 wks (maybe 22wks)
what are the parts of G-protein coupled receptors (GPCRs)?
receptor
3 G proteins = alpha, beta and gamma
enzyme to make second messenger (cAMP)
what are the G alpha subunits and what do they determine?
G alpha s
G alpha i
G alpha q
they determine what second messenger is made
what does Galpha s do?
positive messenger = makes cAMP
ß2 agonist, PGE2 via EP receptor = uterine relaxation
what does Galpha i do?
negative messenger = prevents cAMP
alpha adrenergic agonists- ergometrine
alpha µ, opioid receptors
PGE2 via EP1 & 3 receptors = uterine contraction - misoprostol
what does Galpha q do?
positive messenger = makes IP3 and DAG
oxytocin receptor, PGF2 via FP2alpha receptor
= uterine contraction, severe PPH - carboprost
how is quiescence maintained?
ß2 agonists, CRH and PGE2 bind to GPCRs with subunit alpha s -> produces cAMP -> produces PKA -> phosphorylation of intracellular proteins -> inactivation of facto-myosin ATPase -> womb contraction blocked = myometrial quiescence
little info about expression of Galpha s is known (de novo synthesis, recycled from membrane compartments)
what are some agonist drugs and how do they work?
ritodrine and salbutamol
increase cAMP = promotes smooth muscle relaxation
promote myocyte hyperpolarisation (open K channels)
tocolytic activity
why do women go into labour when they do?
still unknown
binary switch? placental clock concept CRH/ACTH/HPA axis
fetal derived signal - surfactant proteins
infection = abnormal
how could infection induce labour?
induces inflammatory response in affected tissue - cervix, amnion, placenta, cord, myometrium
premature labour can then be initiated
what pro-inflammatory chemicals are needed in labour?
prostaglandins
cytokines
chemo-attractant cytokine (chemokine)
what is functional progesterone withdrawal?
change in myometrial responsiveness to progesterone
something is blocking pro-quiescent action of progesterone at term - different isoforms of progesterone become dominant
oestrogen activity becomes dominant
local metabolism of progesterone to inactive form
what are the 3 stages of parturition?
cervical dilation - remodelling
fetal expulsion - myometrial contraction
placental delivery - rapid
what pro-inflammatory factors are associated with parturition?
COX-2
IL1ß
IL8
TNF
what happens during cervical ripening?
growth and remodelling of cervix prior to labour
promoted by release of: PGE from cervical mucosa, relaxin, placental oestrogen
effacement and dilation due to muscular action of cervix and uterus = brachystasis -> contractions of fundal myometrium shorten muscle cell length and pull the cervix and lower segment up
how is expression of inflammatory genes controlled?
signal cascade from TNFalpha -> NF-kappaB pathway -> COX-2
what drugs can inhibit the pathways of parturition?
NSAIDS = indomethacin (COX-1) celecoxib (COX-2) corticosteroids = dexamethasone
how does myometrial contractility occur?
inflammation
differential gene expression
elevated calcium - extracellular sources voltage-gated calcium channels
intracellular sources - store-operated channels on sarcoplasmic reticulum
activation of auto-myosin ATPase -> myocyte contraction
what drug inhibits myometrial contraction?
Nifedipine - calcium channel blocker
inhibits premature myometrial contractions
how does oxytocin contribute to parturition?
cervical stimulation/myometrial stretch induces oxytocin secretion (from hypothalamus) -> increased oxytocin receptor numbers seen at term on fundal myometrium
initiates positive feedback mechanism = Ferguson reflex
oxytocin receptors cause signally pathway IP3 -> calcium release from sarcoplasmic reticulum -> intracellular calcium. binding proteins (calmodulin) -> activation of auto-myosin ATPase -> myocyte contraction
what analogues are used to induce labour?
oxytocin = syntocinon
what drugs are used to inhibit oxytocin signalling pathway?
atosiban = oxytocin receptor antagonist, an inhibit premature mymetrial contractions
what other drugs are used to induce myocyte contraction via FPR?
carboprost = prostaglandin analogue
used to treat PPH unresponsive to oxytocin and ergometrine
how does the placental delivery occur?
significant increase in plasma fibrinogen levels and other clotting factors - blood becomes hypercoagulable
at term placental blood flow is 500ml/min and must rapidly block this as exsanguination when placenta separates
when mechanisms are in place to stop rapid blood loss from placental delivery?
rapid myometrial contraction to compress blood vessels
immediate fibrin deposition over placental site
when can depletion of fibrinogen reserve occur?
inadequate myometrial contraction (more common if placenta near lower segment)
incomplete placental separation
how does ergometrine and PGE2 (misoprostol) work?
binds to GPCR with Galphai causing inhibition of cAMP production -> auto-myosin ATPase can contract -> promotes smooth muscle uterine contraction
what enzymes are activated which phosphorylate other cellular proteins to cause myometria quiescence?
protein kinase A and C = PKA, PKC
