Sex- and age-related differences in arterial pressure and albuminuria in mice

Abstract

Background: Animal models have become valuable experimental tools for understanding the pathophysiology and therapeutic interventions in cardiovascular disease. Yet to date, few studies document the age- and sex-related differences in arterial pressure, circadian rhythm, and renal function in normotensive mice under basal conditions, across the life span. We hypothesized that mice display similar sex- and age-related differences in arterial pressure and renal function to humans.

Methods: Mean arterial pressure (MAP) and circadian rhythm of arterial pressure were measured over 3 days via radiotelemetry, in 3- and 5-month-old (adult) and 14- and 18-month-old (aged) FVB/N and in 5-month-old (adult) C57BL/6 male and female normotensive mice. In FVB/N mice, albuminuria from 24-h urine samples as well as body, heart, and kidney weights were measured at each age.

Results: Twenty-four-hour MAP was greater in males than females at 3, 5, and 14 months of age. A similar sex difference in arterial pressure was observed in C57BL/6 mice at 5 months of age. In FVB/N mice, 24-h MAP increased with age, with females displaying a greater increase between 3 and 18 months of age than males, such that MAP was no longer different between the sexes at 18 months of age. A circadian pattern was observed in arterial pressure, heart rate, and locomotor activity, with values for each greater during the active (night/dark) than the inactive (day/light) period. The night-day dip in MAP was greater in males and increased with age in both sexes. Albuminuria was greater in males than females, increased with age in both sexes, and rose to a greater level in males than females at 18 months of age.

Conclusions: Arterial pressure and albuminuria increase in an age- and sex-specific manner in mice, similar to patterns observed in humans. Thus, mice represent a useful model for studying age and sex differences in the regulation of arterial pressure and renal disease. Understanding the mechanisms that underlie the pathophysiology of cardiovascular disease may lead to new and better-tailored therapies for men and women.

Keywords: Aging; Arterial pressure; Hypertension; Menopause; Renal function; Sex.

Fig. 1

Arterial pressures, pulse pressure, heart rate, and locomotor activity in male and female mice at 3, 5, 14, and 18 months of age. a Mean arterial pressure (MAP), b pulse pressure (PP), c systolic arterial pressure (SAP), d diastolic arterial pressure (DAP), e heart rate (HR), and f locomotor activity in male (blue bars) and female (red bars) mice. Data were analyzed using a two-way ANOVA with the factors sex, age, and their interaction. Tukey’s post hoc tests were performed where appropriate. *P < 0.05, **P < 0.01 as compared to age-matched male. ^# P < 0.05, ^## P < 0.01, ^### P < 0.001 as compared to 3-month-old counterpart. ^† P < 0.05, ^††† P < 0.001 as compared to 5-month-old counterpart. ^§ P < 0.05 as compared to 14-month-old counterpart

Fig. 2

Arterial pressures, pulse pressure, heart rate, and locomotor activity in male and female C57BL/6 and FVB/N mice at 5 months of age. a Mean arterial pressure (MAP), b pulse pressure (PP), c) systolic arterial pressure (SAP), d diastolic arterial pressure (DAP), e heart rate (HR), and f locomotor activity in male (blue bars) and female (red bars) mice. Data were analyzed using a two-way ANOVA with the factors sex, strain, and their interaction. Bonferroni’s post hoc tests were performed where appropriate. *P < 0.05, **P < 0.01 as compared to the male of the same strain. ^## P < 0.01 as compared to the C57BL/6 female

Fig. 3

Hourly mean arterial pressure (MAP) and 12-h MAP of the dark and light periods of the day in a, b 3-month-old; c, d 5-month-old; e, f 14-month-old; and g, h 18-month-old male (blue symbols/bars) and female (red symbols/bars) mice. i The change in MAP from the dark to light period of the day in male (blue bars) and female (red bars) mice at 3, 5, 14, and 18 months of age. Shading indicates the 12-h dark/light cycle (lights off at 18:00). Hourly data were analyzed using repeated measured ANOVA with the factors sex, time, and their interaction. Twelve hours data were analyzed using an ANOVA with the factors sex, time, and their interaction followed by Bonferroni’s post hoc tests. The dark/light change in MAP data was analyzed using a two-way ANOVA with the factors sex, age, and their interaction followed by a Tukey’s post hoc tests. ^## P < 0.01, ^#### P < 0.0001 as compared to respective dark period. **P < 0.01, ***P < 0.001, ****P < 0.0001 as compared to respective period in male mice

Fig. 4

Hourly heart rate (HR) and 12-h HR of the dark and light periods of the day in a, b 3-month-old; c, d 5-month-old; e, f 14-month-old, g, h 18-month-old male (blue symbols/bars) and female (red symbols/bars) mice. i The change in HR from the dark to light period of the day in male (blue bars) and female (red bars) mice at 3, 5, 14, and 18 months of age. Shading indicates the 12-h dark/light cycle (lights off at 18:00). Hourly data were analyzed using repeated measured ANOVA with the factors sex, time, and their interaction. Twelve hours data were analyzed using a two-way ANOVA with the factors sex, time, and their interaction followed by Bonferroni’s post hoc tests. The dark/light change in HR data were analyzed using a two-way ANOVA with the factors sex, age, and their interaction followed by a Tukey’s post hoc tests. ^# P < 0.05, ^## P < 0.01, ^### P < 0.001, ^#### P < 0.0001 as compared to respective dark period. **P < 0.01, ***P < 0.001, ****P < 0.0001 as compared to respective period in male mice

Fig. 5

Hourly locomotor activity (activity) and 12-h activity of the dark and light periods of the day in a, b 3-month-old; c, d 5-month-old; e, f 14-month-old; and g, h 18-month-old male (blue symbols/bars) and female (red symbols/bars) mice. i The change in HR from the dark to light period of the day in male (blue bars) and female (red bars) mice at 3, 5, 14, and 18 months of age. Shading indicates the 12-h dark/light cycle (lights off at 18:00). Hourly data were analyzed using repeated measured ANOVA with the factors sex, time, and their interaction. Twelve hours data were analyzed using a two-way ANOVA with the factors sex, time, and their interaction followed by Bonferroni’s post hoc tests. The dark/light change in activity data were analyzed using a two-way ANOVA with the factors sex, age, and their interaction followed by a Tukey’s post hoc tests. *P < 0.05 as compared to respective period in male mice. ^# P < 0.05, ^## P < 0.01, ^#### P < 0.0001 as compared to respective dark period

Fig. 6

Body weight, organ weights, and albuminuria in male (blue bars) and female (red bars) mice at 3, 5, 14, and 18 months of age. a Body weight (BW), b heart weight, c heart weight to BW ratio, d total kidney weight, e total kidney weight to BW ratio, and f albuminuria. Data were analyzed using a 2-way ANOVA with the factors sex, age and their interaction. Tukey post hoc tests were performed where appropriate. *P < 0.05, **P < 0.01, ****P < 0.0001 as compared to age-matched male. ^# P < 0.05, ^## P < 0.01, ^### P < 0.001, ^#### P < 0.0001 as compared to the 3-month-old counterpart. ^† P < 0.05, ^†† P < 0.01, ^††† P < 0.001, ^†††† P < 0.001 as compared to the 5-month-old counterpart. ^§P < 0.05, ^§§P < 0.01, ^§§§§P < 0.0001 as compared to the 14-month-old counterpart