Long Lasting Microvascular Tone Alteration in Rat Offspring Exposed In Utero to Maternal Hyperglycaemia

Abstract

Epidemiologic studies have demonstrated that cardiovascular risk is not only determined by conventional risk factors in adulthood, but also by early life events which may reprogram vascular function. To evaluate the effect of maternal diabetes on fetal programming of vascular tone in offspring and its evolution during adulthood, we investigated vascular reactivity of third order mesenteric arteries from diabetic mother offspring (DMO) and control mother offspring (CMO) aged 3 and 18 months. In arteries isolated from DMO the relaxation induced by prostacyclin analogues was reduced in both 3- and 18-month old animals although endothelium (acetylcholine)-mediated relaxation was reduced in 18-month old DMO only. Endothelium-independent (sodium nitroprusside) relaxation was not affected. Pressure-induced myogenic tone, which controls local blood flow, was reduced in 18-month old CMO compared to 3-month old CMO. Interestingly, myogenic tone was maintained at a high level in 18-month old DMO even though agonist-induced vasoconstriction was not altered. These perturbations, in 18-months old DMO rats, were associated with an increased pMLC/MLC, pPKA/PKA ratio and an activated RhoA protein. Thus, we highlighted perturbations in the reactivity of resistance mesenteric arteries in DMO, at as early as 3 months of age, followed by the maintenance of high myogenic tone in older rats. These modifications are in favour of excessive vasoconstrictor tone. These results evidenced a fetal programming of vascular functions of resistance arteries in adult rats exposed in utero to maternal diabetes, which could explain a re-setting of vascular functions and, at least in part, the occurrence of hypertension later in life.

Maternal Diabetes Mellitus and Persistent Pulmonary Hypertension of the Newborn: Accumulated Evidence From Observational Studies

“…The PGI2/IP interaction stimulates G protein-coupled receptors, leading to vascular smooth muscle relaxation (45). Reduction of PGI2dependent relaxation has been reported among offspring of rats with diabetes, which was associated with a decrease in IP receptor expression level (46). Diabetic hyperglycemia also results in elevated glucose levels in fetus, causing excess fetal insulin production (hyperinsulinism) (47).…”

The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment

“…In utero exposure to adverse intrauterine environment (e.g., by maternal malnutrition, obesity, toxin exposure, or diabetes) during the critical period of embryogenesis could significantly affect adult phenotype of offspring, [3][4][5]36,37 known as fetal programming. 38 In particular, the effects of in utero exposure to maternal diabetes on offspring health are under intensive inspection because the number of diabetic female at childbearing age is overwhelmingly increasing.…”

“…Pregnancy complicated by diabetes is gaining attention as the number of childbearing women with diabetes is mounting due to the childhood obesity epidemic . Experimental and human studies indicate that in utero exposure to maternal diabetes not only predisposes the fetus to adverse outcomes including macrosomia, stillbirth, intrauterine growth restriction, and congenital malformations, but also increases the risk of major diseases in the adult offspring including metabolic disorders, renal dysfunction, hypertension, and vascular dysfunction . Notably, a recent human study demonstrated that adolescent offspring of diabetic mothers presented significantly higher cardiosympathetic reactivity to laboratory stressors .…”

“…1 Experimental and human studies indicate that in utero exposure to maternal diabetes not only predisposes the fetus to adverse outcomes including macrosomia, stillbirth, intrauterine growth restriction, and congenital malformations, 2 but also increases the risk of major diseases in the adult offspring including metabolic disorders, renal dysfunction, hypertension, and vascular dysfunction. [3][4][5] Notably, a recent human study demonstrated that adolescent offspring of diabetic mothers presented significantly higher cardiosympathetic reactivity to laboratory stressors. 6 Considering that greater cardiovascular response to laboratory stimuli is associated with higher cardiovascular a These authors contributed equally to this work.…”

Reduced expression of PMCA1 is associated with increased blood pressure with age which is preceded by remodelling of resistance arteries

“…The observation of elevated tone in arteries from young and aged PMCA1 Ht mice, compared to age‐matched WT animals, is consistent with the notion that PMCA1 may contribute to the development and maintenance of hypertension. Herein, we show a small reduction in the magnitude of basal tone with age, an effect which has been previously noted in mesenteric arteries and in arterioles isolated from the gastrocnemius and soleus muscles of rats (Kang et al ., ; Vessieres et al ., ). Such an age‐related change has not been associated with an elevation of BP in rats (Kang et al ., ), comparable to aging WT mice used in this study.…”