Parental obesity alters offspring blood pressure regulation and cardiovascular responses to stress: role of P2X7R and sex differences

Abstract

We examined the impact of parental obesity on offspring blood pressure (BP) regulation and cardiovascular responses to stress. Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diet (HH). Body weight, calorie intake, and fat mass were measured at 22 wk of age when cardiovascular phenotyping was performed. Male and female HH offspring were 15% heavier than NH and 70% heavier than NN offspring. Male HH and HN offspring had elevated BP (121 ± 2 and 115 ± 1 mmHg, by telemetry) compared with male NH and NN offspring (108 ± 6 and 107 ± 3 mmHg, respectively) and augmented BP responses to angiotensin II, losartan, and hexamethonium. Male HH and HN offspring also showed increased BP responses to air-jet stress (37 ± 2 and 38 ± 2 mmHg) compared with only 24 ± 3 and 25 ± 3 mmHg in NH and NN offspring. Baseline heart rate (HR) and HR responses to air-jet stress were similar among groups. In females, BP and cardiovascular responses to stress were similar among all offspring. Male H diet-fed offspring from obese H diet-fed purinoreceptor 7-deficient (HH-P2X7R-KO) parents had normal BP that was similar to control NN-P2X7R-KO offspring from lean parents. These results indicate that parental obesity leads to increased BP and augmented BP responses to stress in their offspring in a sex-dependent manner, and the impact of parental obesity on male offspring BP regulation is markedly attenuated in P2X7R-KO mice.

Keywords: baroreflex; developmental programming; heart rate variability; hypertension; purinoreceptor.

Figure 1.

Metabolic phenotype of male and female offspring from lean and obese parents. Body weight (A), calorie intake (B), and fat mass in male offspring (C); body weight (D), calorie intake (E), and fat mass in female offspring (F) from lean and obese parents. [n = 5–8 offspring from 5 to 7 dams/group, *P < 0.05 vs. NN offspring (one-way ANOVA), #P < 0.05 vs. NH offspring (one-way ANOVA)]. H, high-fat; HH, offspring from obese (H) parents that were also fed an H diet after weaning; HN, offspring from obese (H) parents that were fed N diet after weaning; N, normal; NH, offspring from lean (N) parents that were fed high-fat (H) diet after weaning; NN, offspring from lean normal (N) diet-fed parents that were also fed an N diet after weaning.

Figure 2.

Cardiovascular phenotype of male and female offspring from lean and obese parents. Circadian variation in mean arterial pressure (MAP; A), average MAP (B), and frequency distribution of systolic blood pressure (BP; C) in male offspring; circadian variation in MAP (D), average MAP (E), and frequency distribution of systolic BP (F) in female offspring; % dipping (G), heart rate (HR; H), and spontaneous baroreflex sensitivity (sBRS; I) in male offspring; % dipping (J), HR (K), and sBRS (L) in female offspring from lean and obese parents. [n = 5–9 offspring from 5 to 7 dams/group, *P < 0.05 vs. NN offspring (one-way ANOVA), #P < 0.05 vs. NH offspring (one-way ANOVA)]. H, high-fat; HH, offspring from obese (H) parents that were also fed an H diet after weaning; HN, offspring from obese (H) parents that were fed N diet after weaning; N, normal; NH, offspring from lean (N) parents that were fed high-fat (H) diet after weaning; NN, offspring from lean normal (N) diet-fed parents that were also fed an N diet after weaning.

Figure 3.

Mean arterial pressure (MAP) and heart rate (HR) responses to acute stress in male and female offspring from lean and obese parents. Δ MAP (A), peak MAP (B), area under curve (AUC) MAP during stress (C), AUC MAP poststress (D) in male offspring; Δ MAP (E), peak MAP (F), AUC MAP during stress (G), and AUC MAP poststress (H) in female offspring; Δ HR in male offspring (I) and Δ HR in female offspring (J) from lean and obese parents. [n = 5 or 6 offspring from 5 to 6 dams/group, *P < 0.05 vs. NN offspring (one-way ANOVA)]. H, high-fat; HH, offspring from obese (H) parents that were also fed an H diet after weaning; HN, offspring from obese (H) parents that were fed N diet after weaning; N, normal; NH, offspring from lean (N) parents that were fed high-fat (H) diet after weaning; NN, offspring from lean normal (N) diet-fed parents that were also fed an N diet after weaning.

Figure 4.

Change in mean arterial pressure (MAP) induced by intraperitoneal administration of losartan (5 mg/kg), angiotensin II (10 ng), and hexamethonium (30 mg/kg) in male offspring from lean and obese parents. Delta and percentage changed in MAP in response to losartan (A), angiotensin II (B), and hexamethonium (C). [n = 5 or 6 offspring from 5 to 6 dams/group, *P < 0.05 vs. NN offspring (one-way ANOVA) and #P < 0.05 vs. NH offspring (one-way ANOVA)]. H, high-fat; HH, offspring from obese (H) parents that were also fed an H diet after weaning; HN, offspring from obese (H) parents that were fed N diet after weaning; N, normal; NH, offspring from lean (N) parents that were fed high-fat (H) diet after weaning; NN, offspring from lean normal (N) diet-fed parents that were also fed an N diet after weaning.

Figure 5.

Expression of P2X7R in the kidneys and metabolic phenotype of male and female P2X7R-deficient (P2X7R-KO) offspring from lean and obese P2X7R-KO parents. P2X7R protein expression (A), body weight (B), calorie intake (C), and fat mass (D) in male offspring; P2X7R protein expression (E), body weight (F), calorie intake (G), and fat mass (H) in female offspring from lean and obese parents. [n = 5 offspring from 5 dams/group, #P < 0.05 vs. NN and NH offspring (one-way ANOVA), *P < 0.05 vs. NN-P2X7R-KO offspring (unpaired two-tailed t test)]. H, high-fat; HH, offspring from obese (H) parents that were also fed an H diet after weaning; HN, offspring from obese (H) parents that were fed N diet after weaning; N, normal; NH, offspring from lean (N) parents that were fed high-fat (H) diet after weaning; NN, offspring from lean normal (N) diet-fed parents that were also fed an N diet after weaning.

Figure 6.

Cardiovascular phenotype of male and female P2X7R-deficient (P2X7R-KO) offspring from lean and obese P2X7R-KO parents. Circadian variation in mean arterial pressure (MAP; A), average MAP (B), and frequency distribution of systolic blood pressure (BP; C) in male offspring; circadian variation in MAP (D), average MAP (E), and frequency distribution of systolic BP (F) in female offspring; heart rate (HR) in male (G), and HR in female (H) offspring from lean and obese P2X7R-KO parents. (n = 5 offspring from 5 dams/group). H, high-fat; HH-P2X7R-KO, offspring from obese high-fat (H) diet-fed P2X7R-KO parents that were also fed an H diet after weaning; NN-P2X7R-KO, offspring from lean normal (N) diet-fed P2X7R-KO parents that were also fed an N diet after weaning.

Figure 7.

Mean arterial pressure (MAP) and heart rate (HR) responses to acute stress in male and female P2X7R-deficient (P2X7R-KO) offspring from lean and obese P2X7R-KO parents. Δ MAP (A), peak MAP (B), area under curve (AUC) MAP during stress (C), and AUC MAP poststress (D) in male offspring; Δ MAP (E), peak MAP (F), AUC MAP during stress (G), and AUC MAP poststress (H) in female offspring; Δ HR in male offspring (I) and Δ HR in female offspring (J) from lean and obese P2X7R-KO parents. (n = 5 offspring/group). HH-P2X7R-KO, offspring from obese high-fat (H) diet-fed P2X7R-KO parents that were also fed an H diet after weaning; NN-P2X7R-KO, offspring from lean normal (N) diet-fed P2X7R-KO parents that were also fed an N diet after weaning.