Marc Q. Mazzuca

Uteroplacental insufficiency causes a nephron deficit, modest renal insufficiency but no hypertension with ageing in female rats

In rats, uteroplacental insufficiency induced by uterine vessel ligation restricts fetal growth and impairs mammary development compromising postnatal growth. In male offspring, this results in a nephron deficit and hypertension which can be reversed by improving lactation and postnatal growth. Here, growth, blood pressure and nephron endowment in female offspring from mothers which underwent bilateral uterine vessel ligation (Restricted) on day 18 of pregnancy were examined. Sham surgery (Control) and a reduced litter group (Reduced at birth to 5, equivalent to Restricted group) were used as controls. Offspring (Control, Reduced, Restricted) were cross‐fostered on postnatal day 1 onto a Control (normal lactation) or Restricted (impaired lactation) mother. Restricted‐on‐Restricted offspring were born small but were of similar weight to Control‐on‐Control by postnatal day 35. Blood pressure was not different between groups at 8, 12 or 20 weeks of age. Glomerular number was reduced in Restricted‐on‐Restricted offspring at 6 months without glomerular hypertrophy. Cross‐fostering a Restricted pup onto a Control dam resulted in a glomerular number intermediate between Control‐on‐Control and Restricted‐on‐Restricted. Blood pressure, along with renal function, morphology and mRNA expression, was examined in Control‐on‐Control and Restricted‐on‐Restricted females at 18 months. Restricted‐on‐Restricted offspring did not become hypertensive but developed glomerular hypertrophy by 18 months. They had elevated plasma creatinine and alterations in renal mRNA expression of transforming growth factor‐β1, collagen IV (α1) and matrix matelloproteinase‐9. This suggests that perinatally growth restricted female offspring may be susceptible to onset of renal injury and renal insufficiency with ageing in the absence of concomitant hypertension.

Uteroplacental insufficiency programs regional vascular dysfunction and alters arterial stiffness in female offspring

Intrauterine growth restriction caused by uteroplacental insufficiency increases the risk of cardiovascular disease in adulthood. Vascular mechanisms in female offspring are poorly understood. The aim of this study was to investigate the effects of uteroplacental insufficiency on blood pressure, vascular reactivity and arterial stiffness in four vascular beds in female offspring born growth restricted. Uteroplacental insufficiency was induced on day 18 of gestation in Wistar Kyoto rats by bilateral uterine vessel ligation (Restricted) or sham surgery (Controls). Wire and pressure myography were used to test endothelial and smooth muscle function, and passive mechanical wall properties, respectively, in uterine, mesenteric, renal and femoral arteries of 18‐month‐old female offspring. Collagen and elastin fibres were quantified using circular crossed‐polarized light microscopy and quantitative real time polymerase chain reaction. Restricted female offspring were born 10–15% smaller. Restricted females were normotensive, had plasma triglycerides 2‐fold elevated and had uterine endothelial dysfunction, attributed to a 23% reduction in the maximal relaxation produced by endothelium‐derived hyperpolarizing factor. Uterine artery stiffness was increased, with an augmented proportion of thick and decreased proportion of thin collagen fibres. Vascular reactivity and mechanical wall properties were preserved in mesenteric, renal and femoral arteries in growth restricted females. Female offspring born growth restricted have selective uterine artery endothelial dysfunction and increased wall stiffness. The preserved vascular function in other arteries may explain the lack of hypertension in these females. The uterine artery specific dysfunction has potential implications for impaired pregnancy adaptations and a compromised intrauterine environment of the next generation.

Cardio‐renal and metabolic adaptations during pregnancy in female rats born small: implications for maternal health and second generation fetal growth

Non‐technical summary  Low weight at birth, or being born small for gestational age, is associated with increased risk of a number of adult diseases, including cardiovascular and kidney disease and diabetes. Generally, low birth weight males have a greater risk of developing such diseases but females do present with subtle changes in organ structure and function that might render them susceptible to lifestyle challenges. We show, for the first time, that low birth weight females have largely normal cardiovascular and kidney adaptations to pregnancy but they do develop altered glucose control. We have shown that their own fetuses are growth restricted suggesting that low birth weight and risk of disease development can be passed on to subsequent generations. These results warrant close monitoring of pregnant women who were born small and shape future studies to focus on therapeutic strategies to minimize the transmission of low birth weight and adult disease risk.

Uteroplacental insufficiency programmes vascular dysfunction in non-pregnant rats: compensatory adaptations in pregnancy

•  Uteroplacental insufficiency programmes uterine vascular dysfunction in female offspring born growth restricted. The vascular adaptations in these female offspring when they in turn become pregnant are poorly understood. •  Females born small and later become pregnant have compensatory vascular adaptations, such that the increased uterine and renal arterial stiffness observed in the non‐pregnant state was resolved in late pregnancy. •  Vascular smooth muscle and endothelial function was normal in pregnant growth restricted female offspring. There was a reduced sensitivity to angiotensin II, but an increased sensitivity to phenylephrine in uterine arteries during pregnancy, and enhanced endothelium‐mediated relaxation in uterine and mesenteric arteries. Importantly, arteries of growth restricted females adapted to these changes. •  Pregnancy was associated with increased outside and internal diameters in uterine and mesenteric arteries, but not renal and femoral arteries, and being born growth restricted did not alter this process. •  These findings may assist our understanding of the maternal vascular adaptations to pregnancy in growth restricted female offspring.

Uteroplacental insufficiency temporally exacerbates salt-induced hypertension associated with a reduced natriuretic response in male rat offspring

Low weight at birth increases the risk of developing chronic diseases in adulthood A diet that is high in salt is known to elevate blood pressure, which is a major risk factor for cardiovascular and kidney diseases The present study demonstrates that growth restricted male rats have a heightened sensitivity to high dietary salt, in the context of raised systolic blood pressure, reduced urinary sodium excretion and stiffer mesenteric resistance vessels Other salt‐induced effects, such as kidney hyperfiltration, albuminuria and glomerular damage, were not exacerbated by being born small The present study demonstrates that male offspring born small have an increased cardiovascular susceptibility to high dietary salt, such that that minimizing salt intake is probably of particular benefit to this at‐risk population

Angiotensin receptor blockade in juvenile male rat offspring: Implications for long-term cardio-renal health

Graphical abstract Figure. No caption available. &NA; Inhibition of the renin‐angiotensin system in early postnatal life is a potential therapeutic approach to prevent long‐term cardiovascular and kidney diseases in individuals born small. We determined the long‐term effects of juvenile losartan treatment on cardiovascular and kidney function in control male rat offspring and those exposed to uteroplacental insufficiency and born small. Bilateral uterine vessel ligation (Restricted) or sham (Control) surgery was performed in late gestation in Wistar Kyoto rats. At weaning, male offspring were randomly assigned to receive losartan in their drinking water or drinking water alone from 5 to 8 weeks of age, and followed to 26 weeks of age. Systolic blood pressure and kidney function were assessed throughout the study. Pressure myography was used to assess passive mechanical wall properties in mesenteric and femoral arteries from 26‐week‐old offspring. Losartan treatment for three weeks lowered systolic blood pressure in both Control and Restricted groups but this difference was not sustained after the cessation of treatment. Losartan, irrespective of birth weight, mildly increased renal tubulointerstitial fibrosis when assessed at 26 weeks of age. Mesenteric artery stiffness was increased by the early losartan treatment, and was associated with increased collagen and decreased elastin content. Losartan also exerted long‐term increases in fat mass and decreases in skeletal muscle mass. In this study, untreated Restricted offspring did not develop hypertension, vascular dysfunction or kidney changes as anticipated. Regardless, we demonstrate that short‐term losartan treatment in the juvenile period negatively affects postnatal growth, and kidney and vascular parameters in adulthood, irrespective of birth weight. The long‐term effects of early‐life losartan treatment warrant further consideration in settings where the potential benefits may outweigh the risks; i.e. when programmed adulthood diseases are apparent and in childhood cardiovascular and kidney diseases.