Lecture 18; Fetal origins of cardiovascular disease. Flashcards
What if fetal programming?
An adverse factor during a critical stage of development alters or programmes the development of fetal tissue, which enables the fetus to survive, but with adverese consequences in post natal life.
What are adverse factors?
- Genetic
- Epigenetic
- Environmental (intrauterine and postnatal) factors
Describe the various factors that can influence the developing fetus;
Maternal; - nutrition - smoking - stress - infection (i.e peridontal disease!) Maternal-fetal endocrine disturbance
(Adverse environmental cues from mother are signalled to the developing fetus)
leads to adaptive response
What can the adaptive response result in?
The adaptive response can lead to;
- Growth restriction = low birth weight (can also contribute / lead to below)
or
- altered metabolic/physiological profile
= Disease in adult life
What have extensive epidemiological studies shown regarding low birthweight?
Extensive epidemiological studies have shown that low birth weight, a marker for intrauterine adversity, is associated with hypertension, type II diabetes, the metabolic syndrome and the development of cardiovascular disease in later life
What is the barker hypothesis?
A number of chronic diseases have their origins in early fetal life
i.e
Hypertension
Type 2 Diabetes
Coronary Artery Disease
Low birth weight + later disease = fetal programming
What did the american nurses’ study show?
- birth weight and mortality from cardiovascular disease are inversely associated in adult women
- birth weight and risk of non-fatal cardiovascular disease and stroke is also inversely associated in adult women
Associations not altered by socioeconomics as a child or adult lifestyle factors
Describe low birth weight and HPA function;
Low birth weight is associated with increased plasma cortisol (indicates overactive adrenal axis)
Men small at birth show increased adrenocortical responses to synthetic ACTH
Describe fetal reprogramming mechanisms
Very complex
Two mechanisms have been postulated to be important in glucocorticoid fetal programming of hypertension.
Describe the first mechanism of fetal reprogramming;
Suboptimal placental or maternal nutrient supply – this results in increased GC (glucocorticoids) – restrict fetal growth, programs permanent changes in cardiovascular, endocrine & metabolic systems
Describe the second mechanism of fetal reprogramming;
Exposure to excess maternal/exogenous glucocorticoids
Describe how fetal overexposure to GC can occur;
Adverse maternal environment=
- High maternal GC concentration
- Reduced 11B-HSD2
or
Exogenous GC
- Inhibition of 11B-HSD2
What does fetal overexposure to GC lead to, using a summery flow diagram;
Fetal overexposure to GC=
- Epigenitic change i.e methylation changes
- Fetal adaptation
(genetic factors influence this anyway)
therefore
- Changes in organ structure
- Changes in Gene expression
Thus leading to;
Hypertension
type 2 diabetes
(not helped by adult postnatal environment i.e smoking, obesity, excess salt)
Describe fetal cortisol levels;
- During fetal life GCs are low cf. to maternal GCs.
- Maternal GC, circulate at levels 5-1000 times > fetus.
- Fetal GCs generally increase steadily with increasing gestational age.
What happens when the fetus is exposed to high maternal of exogenous GC?
Study One
Excessive exposure of the fetus to maternal or exogenous GC: (dangerous if during critical times)
low birthweight, alters maturation of organs
may have lasting or lifelong effects such as late-onset hypertension in adult life
Note; 11 studies to give evidence for GC exposure, altered HPA, hypertension interelationships
Why are GCs bad?
Glucocorticoids (GCs): Potent regulators of fetal growth and development
Describe the action of GCs;
GCs; Switch the cell cycle from ACCRETION (continuous cell growth) to MATURATION/DIFFERENTIATION in most tissues i.e - lungs – Kidney – Gut/intestines – Neuronal/brain – Cardiovascular system
Thus excess GCs are thought to play an impt. role in fetal programming.
What normally prevents the high maternal GC’s from crossing the placenta?
They can easily cross because they are lipophilic. SO how can we have low fetal GCs but high maternal?
11 beta hydroxysteroid dehydrogenase 2
- Converts cortisol to cortisone (inactive)
- Highly expressed in the placental barrier to protect the fetus from overexposure to maternal GCs
- Regulation of cortisol at the cellular level
11 beta hydroxysteroid reductase 1 reverses cortisone into cortisol
What can inhibit 11B-HSD2?
Carbenoxolone
What do studies using cabrenoxolone show?
Study 2
Prenatal Inhibition of 11b-HSD 2 in rats by carbenoxolone (CBX) produces permanent hypertension, neuroendocrine, metabolic abnormalities in adult life
Low placental 11b-HSD2 hence increased transplacental passage of maternal GCs correlates with lower birth weight
Which other study supports maternal/exogenous GC in programming of hypertension?
Study 3
Studies using Metyrapone
and
Maternal adrenalectomy:
Describe what the results were using metyrapone;
Study 3a
Metyrapone: inhibitor of adrenal GC production
• Maternal admin. prevents hypertension in offspring of undernourished mothers (rats)
But not selective since both fetal and maternal GC production is affected.
Describe what the studies using maternal adrenalectomy showed;
Study 3B
Prevents hypertension in offspring of undernourished mothers (rats).
How else could fetal GC exposure be raised? other that impaired placental 11B-HSD2?
1) Altered fetal 11B-HSD activity i.e diminished tissues 11B-HSD2 kidney or increased 11B-HSD1 in adipose tissue and thus accumulation of GCS in tissues
2) Altered fetal HPA activity (increased cortisol production (negative feedback to stop it)
What enzyme altered at the tissue level would result in increased cortisol?
11B-HSD1 increased in tissues (adipose) would increase the extra adrenal production of cortisol
Whats the link between HPA, Birth weight, blood pressure and fetal reprogramming
Study 4
Programming of the HPA axis by events in fetal life may be one of the mechanisms linking reduced size at birth with raised blood pressure in later life.
Adverse events in fetal life=
Altered HPA feedback=
Increased activity of the HPA=
Increased risk of adult hypertension and metabolic diseases.
what does epidemiological studies suggest about HPA function and low birth weight
Study 5
Epidemiological findings suggest that low birth weight is associated with increased HPA activity in adulthood and that this could contribute to the risk of cardiovascular disease.
Describe exactly how GC exposure can reprogram HPA function
Study 6
Evidence suggests that overexposure to maternal GCs programmes the fetal HPA axis resulting in lower levels of glucocorticoid receptors in the hypothalamus and pituitary, which may impair negative feedback control of CRH and ACTH and result in increased secretion of cortisol in fetal life and postnatal life.
Alternatively, reduction of hippocampal GR and MR may enhance hyperactivity of the HPA.
But what are the exact mechanisms by which GCs are involved in the programming of hypertension?
The mechanisms are still not completely clear and are probably multifaceted
Describe option one for the possible mechanistic pathways in GC fetal programming of hypertension;
option 1
- Overactivity of renin-angiotensin system (RAS) or altered activity of key enzymes of RAS
Describe option two for the possible mechanistic pathways in GC fetal programming of hypertension;
option 2
- Abnormalities of renal development e.g.
– Decreased nephron number
– Upregulation of sodium channels (promotes salt and H2O retention postnatally)
Describe option three for the possible mechanistic pathways in GC fetal programming of hypertension;
option 3
- Increased production of reactive oxygen species
Describe option four for the possible mechanistic pathways in GC fetal programming of hypertension;
option 4
- Increased sympathetic nervous system activity
Describe option five for the possible mechanistic pathways in GC fetal programming of hypertension;
option 5
- Altered vasoactive responses
Describe ANG2 effects;
- Production of Ang II can lead to a twofold effect on blood pressure via enhanced renal reabsorption of H2O (increasing blood volume) and enhanced systemic vasoconstriction via the AT1 receptor (increasing peripheral resistance).
- This is offset via the effects of ACE 2 leading to the production of ANG-[1–7] and activation of the Mas (G protein-coupled receptor Mas) and AT2 receptors.
Describe the rat animal model effects of fetal glucocorticoid exposure;
Study 7 (rat+corticosterone)
• Maternal admin. GC (Corticosterone) Results in offspring with:
– decrease in nephron number
– ↑ BP
– ↑ AT1 and AT2 expression in the peripheral tissues
– Note:↑ gene expression of AT1R thought to occur in glomeruli of kidney but wasn’t confirmed
Describe the spiny mouse animal model effects of fetal synthetic glucocorticoid (dexamethasone) exposure;
Study 8
Showed upregulation of key branching morphogenesis genes in the fetal kidney that leads to a permanent nephron deficit in the adult offspring. (potential cause of hypertension)
Describe the findings of prenatal GCs exposure in sheep findings; looking at kidney structure
Study 9
What they did:
• Dexamethasone or cortisol (26-28 days gestn to maternal sheep)
What they found:
- ↓ nephron number occurs before birth
- ↑ sodium channels in kidney (ENaC-a,β,g) → mechanistic link to sustained increases in arterial pressure
Describe what the study on induced fetal reprogamming in sheep found; looking at RAAS
Study 10
What they did:
• Betamethasone (80 days gestn to maternal sheep)
What they found:
• Postnatally, an increase in ratio of AT1/AT2 receptors in kidney associated with an increased response in the Ang II-dependent release of reactive oxygen species (ROS). Such changes might contribute to the sustained BP observed in fetal programming (this wasnt seen in the rats!!!)
Describe what was found when fetal ACE and Renin levels were altered;
Study 11
What they did:
• Betamethasone (at 80 days gestn sheep)
• Analysed offspring at
1.8 postnatal years
Conclusion:
Betamethasone:
• higher serum ACE activity but lower serum ACE2 activity - supports a shift toward greater synthesis (ACE) and reduced metabolism (ACE2) of Ang II, as well as reduced formation of Ang-(1-7) which potentially acts as a vasodilator (formed in blood vessels). The alterations in the ratio of these peptides would favour an elevation of blood pressure.
Also found (not shown here) reduced ACE2 activity within the adult kidney of betamethasone-treated sheep
How do synthetic GCs exposure alter fetal development different between genders? (what they did)
Betamethasone (80 days gestn to maternal sheep)
How do synthetic GCs exposure alter fetal development different between genders? (findings 1)
Vascular sensitivity to ET-1 was increased specifically in female offspring from betamethasone- treated sheep
NB ET-1 produced by vascular endothelial cells causes vasoconstriction
How do synthetic GCs exposure alter fetal development different between genders? (findings 2)
betamethasone caused sex- specific effects (males only affected) on renal function and salt handling (a precursor to high blood pressure) in ewes and rams at 1.5 yr of age
Seriously learn the final diagram slide that links it all together
do it if you have time
