Prenatally programmed hypertension: role of maternal diabetes

Gomes, Guiomar Nascimento; Gil, Frida Zaladek

doi:10.1590/s0100-879x2011007500109

Cited by 12 publications

(4 citation statements)

References 58 publications

(63 reference statements)

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“…Studies in rats demonstrate that male but not female offspring of dams made diabetic prior to mating or on the 7th day of pregnancy are hypertensive by 2–3 months of age 12–14 . Findings of these studies and others suggest changes in baroreflex sensitivity, vascular responsiveness, activity of the renin-angiotensin and NO systems and arachidonic acid metabolism may contribute to the development of hypertension in ODM 15,16 . Because gestational onset diabetes, characterized by maternal hyperglycemia during the last third of gestation, is the most common form of diabetes to affect pregnancy, our laboratory has focused on a rat model whereby maternal hyperglycemia is induced by streptozotocin at the beginning of the third and final week of gestation.…”

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confidence: 87%

Sex-specific programming of hypertension in offspring of late-gestation diabetic rats

et al. 2012

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Background The intrauterine environment strongly influences adult disease susceptibility. We utilized a rat model of third trimester maternal diabetes to test the hypothesis that adult offspring exposed to hyperglycemia in utero display increased blood pressure and alterations in vascular responsiveness. Methods Diabetes was induced by streptozotocin injection to pregnant rats on gestation day 13 (term 21 day) and partially controlled with insulin injections. Hemodynamic function was evaluated in 6–12 month old offspring. Results Male but not female offspring of diabetic mothers (ODM) had significantly increased blood pressure compared to controls, heart rate was similar. For both sexes, heart rate baroreflex responses were similar as were in vivo hemodynamic responses to angiotensin II, NOS inhibition and ganglionic blockade. Aortic contractility to angiotensin II was similar in both groups. NOS inhibition and the Cu/Zn superoxide dismutase (SOD) inhibitor diethyldithiocarbamate but not the SOD-mimetic Tempol significantly increased contractile responses to angiotensin II in controls but not ODM. NADPH stimulated superoxide production was greater in male ODM than controls (p<0.05). Conclusions Exposure to hyperglycemia in utero results in sex specific cardiovascular changes in adult offspring. Impaired NO - reactive oxygen species signaling may play a significant role in the hemodynamic phenotype of ODM.

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confidence: 87%

Sex-specific programming of hypertension in offspring of late-gestation diabetic rats

et al. 2012

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“…Environmental perturbations during pregnancy predispose offspring to altered vascular function, leading to hypertension [ 6 , 7 , 8 , 9 ] and cardiovascular disease later in life [ 10 ]. It is well known that the vascular tone of small arteries (i.e.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…Mesenteric arteries of 3-month old CMO and DMO rats were split into 4 groups and incubated at 37°C during 24 h in 100 μL buffer containing Leibovitz medium with 10% fetal bovine serum, a mix of antibiotic-antimycotic solution (1%, 15240062, Gibco, Courtaboeuf, France), Dapi (5 μg/mL, Molecular Probes, Carlsab, USA) and either Alexa Fluor594/Cadaverine (10 μmol/L, A-30678, Invitrogen, Carlsab, USA), or (Aceti et al, 2012 ) Alexa Fluor594/Cadaverine + SNP ( 10 −3 mol/L), or (Bunt et al, 2005 ) Alexa Fluor594/Cadaverine + dithiothreitol (DTT, 2 mmol/L, 43816, Sigma, St Quentin Fallavier, France), or (Gomes and Gil, 2011 ) Alexa Fluor594/Cadaverine + DTT (2 mmol/L) + SNP (10 −3 mol/L). Vessels were mounted on Mowiol and imaged on a confocal microscope (Nikon Eclipse TE2000S).…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, the relationship between in utero exposure to maternal diabetes and the incidence of cardiovascular diseases in offspring, and especially that of hypertension, has been the subject of clinical and experimental studies. Indeed, numerous works show that offspring of diabetic mothers have a higher systolic blood pressure (SBP) than offspring of control mothers (Bunt et al, 2005 ; Rocha et al, 2005 ; Wichi et al, 2005 ; Nehiri et al, 2008 ; Gomes and Gil, 2011 ; Aceti et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Prenatally programmed hypertension: role of maternal diabetes

Cited by 12 publications

References 58 publications

Sex-specific programming of hypertension in offspring of late-gestation diabetic rats

Sex-specific programming of hypertension in offspring of late-gestation diabetic rats

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

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

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