Maternal hyperleptinemia is associated with male offspring’s altered vascular function and structure in mice

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Lepr db/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under astandard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post-natal environments to contribute to altered vascular function in offspring of diabetic pregnancie

Effect of maternal environment and offspring diet on the mechanical properties of mesenteric resistance arteries from adult (31 week-old) wild type (WT) male offspring of WT-control or Lepr^db/+ (db/+) dams.

<p>(A-D) Strain-stress relationship curves of mesenteric arteries kept under passive conditions at different intravascular pressures. (E-H) Elastic moduli of mesenteric arteries kept under passive conditions at different intravascular pressures. (I-L) Compliance of mesenteric arteries kept under passive conditions at different intravascular pressures. The shaded areas represent the data used to calculate the elastic moduli at low pressures, which are shown in the insets. Data are means ± SEM of n = 5–7 number of animals (vessels) per treatment group combination. *<i>P</i><0.05. SD, standard diet; HFD, high fat diet.</p

Experimental Design.

<p>(A) Animal experiments. Blood pressure (BP) and mesenteric artery structure and function were examined in male wild type (WT) offspring of WT-control and hyperleptinemic Lepr^db/+ dams. (B) Protocol to test vascular reactivity in isolated, cannulated and pressurized mesenteric resistance arteries. Two arteries were tested for each mouse. The red and green lines indicate that only one of the arteries from each mouse was exposed to either insulin or acetylcholine. At the end of each experiment all arteries were incubated in calcium-free buffer to obtain maximal passive diameters and subsequently exposed to varying levels of intraluminal pressure.</p

Effect of maternal environment and offspring diet on the structural properties of mesenteric resistance arteries from adult (31 week-old) wild type (WT) male offspring of WT-control or Lepr^db/+ (db/+) dams.

<p>(A-D) Pressure-diameter curves of blood vessels kept under passive conditions. (E-H) Cross sectional area (CSA) of the vascular wall in mesenteric arteries kept under passive conditions at different intravascular pressures. Data are means ± SEM of n = 5–7 number of animals (vessels) per treatment group combination. *<i>P</i><0.05. SD, standard diet; HFD, high fat diet.</p

Effect of maternal environment and offspring diet on the morphological characteristics of mesenteric resistance arteries from adult (31 week-old) wild type (WT) male offspring of WT-control or Lepr^db/+ (db/+) dams.

<p>(A-E) Representative confocal images of mesenteric resistance arteries showing (A) nuclei; (B) F-actin; (C) elastin; (D) collagen; and (E) merged image. (F-H) Group data and representative images showing that feeding a high-fat diet was associated with a significant reduction in arterial F-actin content. (I-K) Group data and representative images showing that feeding a high-fat diet was associated with a significant reduction in arterial elastin content. (L) Vascular smooth muscle cell number, represented by nuclei contained within the medial layer of mesenteric arteries. (M) The amount of collagen contained in the wall of mesenteric arteries. Data are means ± SEM of n = 5–7 number of animals (vessels) per treatment group combination. *<i>P</i><0.05. SD, standard diet; HFD, high fat diet.</p

Effect of maternal environment on the structure and mechanical properties of mesenteric resistance arteries from juvenile (6 week-old) wild type (WT) male offspring of WT-control or Lepr^db/+ (db/+) dams.

<p>(A) Pressure-diameter curves of blood vessels kept under passive conditions. (B) Strain-stress relationship curves of mesenteric arteries kept under passive conditions at different intravascular pressures. (C) Elastic moduli of mesenteric arteries kept under passive conditions at different intravascular pressures. (D) Cross sectional area (CSA) of the vascular wall in mesenteric arteries kept under passive conditions at different intravascular pressures. (E) Vascular wall to intravascular lumen ratio of mesenteric arteries kept under passive conditions at different intravascular pressures. (F) Compliance of mesenteric arteries kept under passive conditions at different intravascular pressures. Data are means ± SEM of n = 5 number of animals (vessels) per treatment group combination.</p

Effect of maternal environment and offspring diet on mesenteric resistance artery responses to acetylcholine and insulin.

<p>All blood vessels were obtained from adult (31 week-old) wild type (WT) male offspring of WT-control or Lepr^db/+ (db/+) dams. (A-D) Acetylcholine-induced vasodilatory responses. (E-H) Insulin-induced vasodilatory responses. Data are means ± SEM of n = 5–6 number of animals (vessels) per treatment group combination. *<i>P</i><0.05. SD, standard diet; HFD, high fat diet.</p

Effect of maternal environment and offspring diet on the internal elastic lamina characteristics of mesenteric resistance arteries from adult (31 week-old) wild type (WT) male offspring of WT-control or Lepr^db/+ (db/+) dams.

<p>(A-D) Representative confocal images of the internal elastic lamina in mesenteric resistance arteries from each of the treatment group combinations. (E-G) Group data showing the number and area of fenestrae within the internal elastic lamina and the elastic modulus of elasticity normalized as a function of the percolation of the internal elastic lamina and its fenestrae. Data are means ± SEM of n = 4–5 number of animals (vessels) per treatment group combination. *<i>P</i><0.05. SD, standard diet; HFD, high fat diet.</p

Effect of maternal environment and offspring diet on mesenteric resistance artery responses to phenylephrine and sodium nitroprusside (SNP).

<p>All blood vessels were obtained from adult (31 week-old) wild type (WT) male offspring of WT-control or Lepr^db/+ (db/+) dams. (A-D) Phenylephrine-induced vasoconstriction responses. (E-H) SNP-induced vasodilatory responses. Data are means ± SEM of n = 5–7 number of animals (vessels) per treatment group combination. SD, standard diet; HFD, high fat diet.</p