In Utero Exposure to Maternal Diabetes Is Associated With Early Abnormal Vascular Structure in Offspring

Abstract

Aim/hypothesis: In utero exposure to maternal diabetes increases the risk of developing hypertension and cardiovascular disorders during adulthood. We have previously shown that this is associated with changes in vascular tone in favor of a vasoconstrictor profile, which is involved in the development of hypertension. This excessive constrictor tone has also a strong impact on vascular structure. Our objective was to study the impact of in utero exposure to maternal diabetes on vascular structure and remodeling induced by chronic changes in hemodynamic parameters.Methods and Results: We used an animal model of rats exposed in utero to maternal hyperglycemia (DMO), which developed hypertension at 6 months of age. At a pre-hypertensive stage (3 months of age), we observed deep structural modifications of the vascular wall without any hemodynamic perturbations. Indeed, in basal conditions, resistance arteries of DMO rats are smaller than those of control mother offspring (CMO) rats; in addition, large arteries like thoracic aorta of DMO rats have an increase of smooth muscle cell attachments to elastic lamellae. In an isolated perfused kidney, we also observed a leftward shift of the flow/pressure relationship, suggesting a rise in renal peripheral vascular resistance in DMO compared to CMO rats. In this context, we studied vascular remodeling in response to reduced blood flow by in vivo mesenteric arteries ligation. In DMO rats, inward remodeling induced by a chronic reduction in blood flow (1 or 3 weeks after ligation) did not occur by contrast to CMO rats in which arterial diameter decreased from 428 ± 17 μm to 331 ± 20 μm (at 125 mmHg, p = 0.001). In these animals, the transglutaminase 2 (TG2) pathway, essential for inward remodeling development in case of flow perturbations, was not activated in low-flow (LF) mesenteric arteries. Finally, in old hypertensive DMO rats (18 months of age), we were not able to detect a pressure-induced remodeling in thoracic aorta.Conclusions: Our results demonstrate for the first time that in utero exposure to maternal diabetes induces deep changes in the vascular structure. Indeed, the early narrowing of the microvasculature and the structural modifications of conductance arteries could be a pre-emptive adaptation to fetal programming of hypertension.

Maternal diabetes during pregnancy and early onset of cardiovascular disease in offspring: population based cohort study with 40 years of follow-up

“…Exposure to hyperinsulinaemia and hyperglycaemia in utero could have longlasting effects on fetal vascular gene expression and result in changes in vascular function, thereby contributing to higher CVD risks in offspring 1532. The results of animal studies3334 indicated abnormalities in vascular reactivity and increased risks of hypertension and cardiovascular dysfunction in offspring of diabetic rats. Several human studies have shown that the diabetic intrauterine environment could have a programming effect on fetal vascular dysfunction, leading to a poor CVD risk profile after birth 1532.…”

Exposure to Maternal Diabetes Mellitus Causes Renal Dopamine D 1 Receptor Dysfunction and Hypertension in Adult Rat Offspring

“…However, the different age of rats and different methods used to determine the number of glomeruli could be the reason of such discrepancy. Several mechanisms have been suggested by which exposure to diabetes in utero causes hypertension in the adult offspring, including: 1) increased activities of the renal renin–angiotensin 37 and sympathetic nerve systems; 38 2) impaired vasorelaxation 39 that may be caused by abnormal aortic arachidonic acid metabolism, including decreased expression of the prostacyclin receptor 40 and impaired nitric oxide-reactive oxygen species (ROS) signaling; 41 and 3) abnormal microvascular structure; 42 and 4) shortened telomere length, 43 as examples. Moreover, a defective sodium handing by the kidney may take an important role because there is a more pronounced increase in the blood pressure of diabetic offspring that received a sodium load.…”

Programmed Adult Kidney Disease: Importance of Fetal Environment

“…Experimental studies in female rats, in which diabetes mellitus was induced before the onset of pregnancy using streptozotocin (STZ), demonstrated that offspring developed glomerular hypertrophy and reduction of both GFR and urinary output (Rocha et al, 2005;Magaton et al, 2007). Additionally, renal vascular resistance and the thickness of interlobular arteries were increased in the offspring of diabetic mothers, suggesting vascular remodeling (Rocco et al, 2008); results recently confirmed by Dib et al (2018). However, there are controversies Frontiers in Physiology | www.frontiersin.org regarding the nephron number in offspring of diabetic mothers (Rocha et al, 2005;Magaton et al, 2007;Rocco et al, 2008).…”