Lecture 18; Fetal origins of cardiovascular disease. Flashcards
(44 cards)
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)
