Team members :
Céline Fassot, Ph.D.
Jennifer Bourreau, Technician
Cyrielle Payen, Ph.D. Student
Cardiovascular disease is one of the greatest health burdens worldwide. Cardiovascular risk is not only determined by conventional risk factors in adult life, but also by early life events resulting in re-setting of key physiological functions. Modifications of the intra-uterine environment during specific windows of fetal development are now recognized as important causes of fetal stress, leading to several responses such as loss of structure/function and pre-emptive adaptations to an adverse post-natal environment, and finally to adult diseases such as metabolic abnormalities and hypertension.
Maternal nutrition is one of the major intrauterine environmental factors that alters expression of the fetal genome and may have lifelong consequences leading to limited physiological function and disease in the offspring. Obesity or diabetes epidemics all around the world induce increased maternal obesity and diabetes during pregnancy. However, if the maternal, obstetric and fetal complications of obese or diabetic women during pregnancy of are well demonstrated, little is known about long-term effects of maternal diabetes or obesity in adult offspring, in particular in term of cardiovascular pathologies.
Several animal models such as modification of maternal nutrition, reduction of uterine supply or glucocorticoids treatment, have contributed to the understanding of some of the mechanisms involved in fetal/perinatal programming by showing that kidney changes and alterations of hormones regulation are involved in the fetal programming of metabolic disorders and hypertension. Alterations of vascular function could be involved in the development of this hypertension. Moreover, one of the most important factors during hypertension is arterial remodeling which allows normalization of wall pressure of arteries but could contribute to cardiovascular disease development later in life.
The aim of our group is to evaluate changes in vascular properties through physiological responses and epigenetic modifications in experimental models of fetal programming.
Thus, we evaluate:
- The epigenetic profile of offspring exposed in utero to maternal metabolic disorders
- Transgenerational effects by studying F2 generation
- Mechanisms implicated in vascular remodeling at physiological and epigenetic levels.
We developed two different models:
1) A rat model of fetal exposure to maternal diabetes (streptozotocin-induced diabetes) characterized by moderate levels of maternal hyperglycemia, normal gestation and delivery with healthy pups without intrauterine growth retardation (IUGR). Our first studies have demonstrated that offspring’s from diabetic mother (DMO) showed a specific gene expression profile in favour of vasoconstriction associated with the development of hypertension around 6 months of age.
The unbalance between vasoactive agents in rats exposed in utero to maternal diabetes is associated with an important decrease of the prostacyclin receptor (IP receptor), inducing a decreased prostacyclin-induced vasodilatation from a pre-hypertensive stage (3 months of age).
2) More recently, we were interested on vascular development in offspring exposed in utero to maternal obesity. It is well known that maternal obesity induces metabolic disorders and vascular reactivity abnormalities in offspring during adulthood. We developed a rat model of maternal obesity (high fat diet) in order to evaluate vascular reactivity at a very early stage, before the onset of metabolic disorder to determinate if fetal programming of vascular function could explain vascular abnormalities observed later in life in these animals.
- Begorre M.A., Dib A., Habchi K., Guihot A.L., BourreauJ., VessieresE., Blondeau B., Loufrani L., Chabbert M., HenrionD., Fassot C. Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes. Scientific Reports.
- VessieresE., DibA., BourreauJ., Lelièvre E., Custaud M.A., Lelievre-PegorierM., Loufrani L., HenrionD., Fassot C. Long Lasting Microvascular Tone Alteration in Rat Offspring Exposed in Utero to Maternal Hyperglycaemia. PLoS One, 2016 ; 11:e0146830
- Blondeau B., Joly B., Perret C., Prince S., Bruneval P., Lelièvre-Pégorier M., Fassot C., Duong Van Huyen J.P. In utero exposure to maternal diabetes leads to glucose intolerance and high blood pressure without major effect on lipid metabolism. Diabetes and Metabolism, 2011 ; 37 : 245-251.
- Duong Van Huyen J.P., Troise A., Perret C., Prince S., Barbry P., Henrion D., Bruneval P., Laurent S., Lelièvre-Pégorier M., Fassot C. Abnormal vascular programming of prostacyclin receptor involved in hypertension in rats exposed in utero to maternal diabetes. Diabetes, 2010 ; 59 : 2597-602.
- Nehiri T., Duong Van Huyen J.P., Viltard M., Fassot C., Heudes D., Freund N., G. Deschênes , Houillier P., Bruneval P. And Lelièvre-Pégorier M. Exposure to maternal diabetes induces salt-sensitive hypertension and impairs renal function in rat offspring. Diabetes, 2008 ;57 : 2167-75.