Vascular Changes in Pregnancy Flashcards
What is the basic vascular structure?
- Endothelial cells line the vessel – blood flows across the endothelium
- ECM of the artery associated with the smooth muscle cells contains elastin – has the ability to contract when the pressure decreases (elastic recoil)
- Contraction and relaxation of smooth muscle cells controlled by endotheium - endothelium doesn’t have contractile force, but sends signals governing the force.
Why is pregnancy often termed an exercise challenge?
• Pregnancy sometimes referred to as an exercise challenge due to the demands placed on the CV system of the woman
• Adaptive mechanisms required of the CVS designed to satisfy one aim → growth of the fetus. Dependent on provision of oxygen and nutrients from the mother.
• Stimuli for changes in CV parametes are metabolic, hormonal and mechanical.
• As pregnancy progresses, progressive increase in blood volume of 35-50% accommodated by:
− Increased CO
− Increased SV
− Increased HR
− Decreased TPVR
• Even though there is increased CO, blood press changes are modest, so where does the CO go?
− Fraction CO to the uterine artery increases from 3.5% early pregnancy, to >12% at term
• Each vascular bed maintains flow in the face of differing local circumstances eg) pressure, hormonal, metabolic or structural changes
What is Poiseuilles Law?
- Volume flowrate → changes with the pressure difference from one end of the vessel to the other, and is also related to the 4th power of the radius (increase radius, VFR increases)
- Resistance to flow → again related to 4th power of the radius, but now on bottom of equation. As you increase radius, resistance to flow decreases.
- → very rapid changes in flow and resistance when you increase the size of the radius
What is the anatomy of the vascular supply to the uterus?
- 2 uterine arteries, one on either side
- Primary branches are the arcuate arteries – branch off like ribs and wrap around the body of the uterus
- Radial arteries branch off from arcuate arteries
- As they progress inward towards the interface between the myometrium and endometrium, they tae on a spiral shape – these are spiral arterioles
- Blood in the endometrium is carried in the spiral arterioles → spirality develops when you get above the endometrial/myometrial boundary.
• The smaller vessels are the dominant vessels contributing to flow resistance
• Regulation of flow is accomplished by dilation and constriction by the arterioles
• During pregnancy, the main uterine artery has altered compliance (softness of the wall) = increased flow can occur as a result
− Compliance = ΔV / ΔP
• The smaller arterioles however, maintain vascular resistance
• Alteration in vascular function in the short to longer term can be mediated by signals from the endothelial cells
What are the endothelium derived vasodilators?
• Prostanoids such as prostacyclin (PGI2)
• Nitric oxide
• Endothelial derived hyperpolarising factor (EDHF)
− Id unknown, but candidates are:
− K+ ions
− EET (an eicosanoid derived from arachidonic acid)
− Cyclic nucleotides
• These effectors can be passed between vascular cells via gap junctions
How does flow through the uterine artery change during pregnancy?
• Major increase in blood flow to the uterus in pregnancy mainly due to dilation of the uterine artery
• Estrogen stimulates NO production by the endothelium, leading to relaxation of VSM
• Specific increase in blood flow in the uterine artery and not other arteries because the uterine artery contains specific receptors for estrogen → so increased estrogen doesn’t affect the vasculature systemically.
• Other endothelial dependent signalling pathways may contribute:
− hCG administered to pigs increases uterine blood flow
− hCG uses the same receptor as LH – so possible LH might have a role
How does flow through the radial artery change during pregnancy?
• Radial artery dilation mechanisms are distinct form the uterine artery
• The contribution of different endothelial derived vasodilators to radial artery relaxation changes during pregnancy:
− Non pregnant → about half the response controlled by NO and half EDHF
− Pregnant → balance has shifted to much more control by EDHF – NO response is attenuated
− This is in contrast to the uterine artery
How does flow through the spiral arterioles change during pregnancy?
• Spiral arterioles feeding the placenta are blocked, structurally remodelled and then reopened in early pregnancy
• Pregnant →
− Arterioles greatly increased in diameter
− Arteries running through both the myometrium and endometrium have grown
− Blood is released into placental vili
− Large arterio-venous shunts form that persist in the immediate post-partum period → these allow for increased diameter of arterioles and uterine artery.
➢ In contrast, in pre-eclampsia, there are minimal arterio-venous shunts.
➢ This gives narrower uterine arteries
− Extra-villous CT invasion in normal pregnancy extends beyond the decidua into the inner myometrium, resulting in the formation of funnels at the discharging tips of the spiral arteries.
What are extravillous trophoblasts and what is their function?
• Distinct population of CT responsible for growth, anchorage and outward migration on ECM
• Anchoring villi attach to the decidua
• At anchoring sites, adhesive CT columns form
• Invasive CTs break off from these and invade the decidua
− Cells excape from the anchoring trophoblast and migrate through the myometrium
− Important in vascular remodelling
− Initially, they form aggregates that plug the openings of spiral arterioles
− This prevents blood from accessing the developing intervillous space
• Trophoblast invasion of the decidua occurs from immediately after implantation, to ~ week 18-20.
Describe the expansion of uteroplacental arteries during pregnancy
• Very large increase in the diameter of the spiral arterioles in the superficial part of the vascular supply → will potentially allow a much greater flow of blood to the fetus, at lower pressure
• At term, the spiral artery is running along the interface between the endometrium and myometrium → the whole uterus is increasing in size, so vessels that were running at right angles to the lumen have been stretched
• Blocking of the spiral arterioles is by CT plugs → blocking is transient, it is in place at 8 weeks byt lost by 16.
− At 8 weeks, there isn’t any flow through the spiral arteries as they are transformed
• Spiral artery remodelling is effected by maternal leukocytes (uterine NK cells and macrophages) in collaboration with trophoblast cells derived from the placenta.
How and why are VSMCs disrupted during pregnancy?
Disruption and loss of VSMCs from spiral arterioles during early pregnancy
• In an un-remodelled artery, there are lots of immune cells around the periphery of the vessel – however they are not yet in the vessel wall
• Early in pregnancy, you get disruption of the VSMCs
− Normally, they are organised circumferentially to give an efficient contractile arrangement
− They get disrupted so they are not in as many layers, and are not oriented in an organised manner.
− This disruption will affect vascular physiology
− Leukocytes are now sitting under the endothelium within the vessel wall → leukocytes get activated to invade the vessel wall, and we think this starts the disruption.
Do factors released by uterine NK cells induces VSMC disruption?
Robson et al, 2012
‘Uterine natural killer cells initiate spiral artery remodelling in human pregnancy;
• uNK cells isolated from decidua and cultured for 24h
• Culture medium (containing secreted factors) transferred into a dissected spiral artery
• 72h later, artery analysed for VSMC orientation
− Hypothesies that uNK cells induce disorganisation and de-differentiation of the VSMCs in the spiral arteries, facilitating entry of the invasive trophoblast
− Indeed, in the nNK medium, you get much more VSMC misalignment
Do trophoblasts effect VSMCs?
- Trophoblast cells make a number of visits to VSMCs, contacting them multiple times
- This has the ability to kill VSMCs
- So part of VSM remodelling is mediated by factors released by uNK cells – but this doesn’t happen unless there is placenta, you need trophoblast killing of VSMCs.
Summarise how VSMCs are remodelled during pregnancy
• So, during the remodelling process, the internal elastic lamina and the media SMCs are removed progressively – first by uNK cells and then by invasive trophoblast
• The ECM is broken down by the uNK cells, leaving a gap for the troph to go into the vessel lumen
• You lose the smooth muscle organisation, and eventually VSMCs disappear all together.
− Loss of the internal elastic lamina and the medial SMCs creates high flow, low resistance channels that lack vasomotor control
− This gets rid of vessel contractility → means the placenta has priorty (placental blood supply privelages)
How long does spiral artery plugging persist and why is it even needed?
- Directly under cord insertion, arteries are plugged
- At this point, there are not maternal blood cells circulating – just plasma fluid
- Laterally, you may see the beginning of dispersion of the plugs – and you are starting to get maternal blood filtering through
- Early on, the embryo is too delicate – if it was subject to the full flow of the maternal blood, it would be displaced, so you need to plug the arteries to protect it
- These plugs are in place for the first 11 weeks – and then they begin to get displaced laterally when the pressure is lower
Summarise the features of hemochorial placentation and how it is remodelled in early pregnancy
- Trophoblast is directly bathed in maternal blood
- The pattern of flow is not fully established until the 11th weeks when the CT plugs are displaced, allowing maternal blood into the intervillous space
- Trophoblast invasion continues to approximately week 18 and proceeds as far as the inner myometrium
- Pre-11 weeks, blood does not flow in the intervillous space of the placenta → fetus and placenta are highly hypoxic at this time
- Meanwhile, the vascular supply is remodelling to avoid exposing the placenta to shear stresses associated with arterial blood pressure
- From 11 weeks, the intervillous space becomes a shunt → oxygenated maternal blood passes through at low pressure
- Arterio-venous shunts also thought to be present in the basal decidua and myometrium
