Fetal programming and cardiovascular pathology

Abstract

Low birth weight serves as a crude proxy for impaired growth during fetal life and indicates a failure for the fetus to achieve its full growth potential. Low birth weight can occur in response to numerous etiologies that include complications during pregnancy, poor prenatal care, parental smoking, maternal alcohol consumption, or stress. Numerous epidemiological and experimental studies demonstrate that birth weight is inversely associated with blood pressure and coronary heart disease. Sex and age impact the developmental programming of hypertension. In addition, impaired growth during fetal life also programs enhanced vulnerability to a secondary insult. Macrosomia, which occurs in response to maternal obesity, diabetes, and excessive weight gain during gestation, is also associated with increased cardiovascular risk. Yet, the exact mechanisms that permanently change the structure, physiology, and endocrine health of an individual across their lifespan following altered growth during fetal life are not entirely clear. Transmission of increased risk from one generation to the next in the absence of an additional prenatal insult indicates an important role for epigenetic processes. Experimental studies also indicate that the sympathetic nervous system, the renin angiotensin system, increased production of oxidative stress, and increased endothelin play an important role in the developmental programming of blood pressure in later life. Thus, this review will highlight how adverse influences during fetal life and early development program an increased risk for cardiovascular disease including high blood pressure and provide an overview of the underlying mechanisms that contribute to the fetal origins of cardiovascular pathology.

Figure 1

Relationship between offspring of women with preeclampsia and systolic blood pressure. (Used with permission, Figure 1, 35).

Figure 2

Measure of MAP in a rat model of IUGR induced by reduced uterine perfusion. Data shown is for both male and female IUGR versus control offspring, at 4, 8, and 12 weeks of age. *P<0.05 vs. male control; †P<0.05 vs. female control; ‡P<0.01 vs. control; and §P<0.01 vs. control. All data are mean±SEM. (Used with permission, Figure 1, 3).

Figure 3

Systolic and diastolic blood pressures in male offspring of control (○, □) or lard-fed dams (•, ▪) at 80, 180, and 360 days old (n=6 for all groups at all-time points). Data are expressed as night (N) and day (D) 12-hour averages over 7 days (1–7). Values are mean±SEM. (Used with permission, Figure 2, 95).

Figure 4

Systolic and diastolic blood pressures in female offspring of control dams (○, □) at 80 days (n=6), 180 days (n=5), and 360 days (n=6) or lard-fed dams (•, ▪) at 80 days (n=6), 180 days (n=5), and 360 days (n=6). Data are expressed as night (N) and day (D) 12-hour averages over 7 days (1–7). Values are mean±SEM. *P<0.05, **P<0.01. (Used with permission, Figure 3, 95).

Figure 5

Influence of current parental smoking on BP in preschool children (**P=0.0001, *P<0.05). The boundary of the box closest to zero indicates the 25th percentile, the line within the box marks the median, and the boundary of the box farthest from zero indicates the 75th percentile. Whiskers (error bars) above and below the box indicate the 90th and 10th percentiles. (Used with permission, Figure 1, .

Figure 6

Effect of nicotine on Ang II–induced BP response in adult male and female offspring. SBP, DBP, and MAP responses to Ang II (10 µg/kg) were measured in adult male and female offspring that had been exposed in utero to saline control or nicotine. Data are means±SEMs and were analyzed by 2-way ANOVA with a posthoc test. *P<0.05, nicotine vs control. (Used with permission, Figure 1, 249).

Figure 7

The effect of chronic Ang II on blood pressure in male and female offspring exposed to early life stress (ELS) relative to control conterpart. ANG II-induced hypertension is delayed and attenuated in female MatSep rats compared with control rats. B*P < 0.05 vs. corresponding sex control group, #P < 0.05 vs. corresponding male group. (Used with permission, Figure 1A, 115).

Figure 8

Systolic blood pressures in 6-month-old rats that received prenatal dexamethasone or vehicle. Blood pressure was taken in trained rats using a tail cuff. Male rats (A) that received prenatal dexamethasone on days 13 and 14, 15 and 16, and 17 and 18 had elevated blood pressure compared with control rats. Female rats (B) were not hypertensive. There are at least 10 male rats in each group. There were 8 female rats in each group except days 11 and 12 and days 19 and 20, in which there were 5 rats. (Used with permission, Figure 5, 151).

Figure 9

The increase of daytime and nighttime SBP with age by ethnicity and gender. (Figure 1, 226).

Figure 10

Serum testosterone levels measured in control and IUGR adult offspring. Blood collection followed decapitation at 16 wk of age. Control intact (n = 17), IUGR intact (n = 16), control CTX (n = 16), and IUGR CTX (n = 15) *P < 0.05 vs. control; †P < 0.05 vs. intact counterpart. All data are expressed as means ± SE. (Used with permission, Figure 5, 145).

Figure 11

The effect of castration on blood pressure in a rat model of intrauterine growth restriction (IUGR) induced by placental insufficiency. Mean arterial pressure (MAP) was measured by radio telemetry from 12 to 16 wk of age in conscious, free-moving animals that underwent either sham (intact) or castration (CTX) at 10 wk of age. Control intact (n = 9), control CTX (n = 8), IUGR intact (n = 8), and IUGR CTX (n = 7). *P < 0.05 vs. control intact; †P < 0.05 vs. IUGR intact. All data are expressed as means ± SE. (Used with permission, Figure 1, 145).

Figure 12

Arterial pressure and renal hemodynamics in adult intact male, castrated (CAS) male and female offspring of rats fed either a normal or protein-restricted diet during pregnancy. Values are means ± SE. *P < 0.05 compared with value for intact males of same diet group. †P < 0.05 compared with value for CAS males. ‡P < 0.05 compared with normal protein animals of same sex group. (Used with permission, Figure 1, 243).

Figure 13

Ovariectomy and blood pressure in IUGR offspring. MAP was measured by radiotelemetry from 12 to 16 weeks of age in animals that underwent either sham (intact) or OVX at 10 weeks of age. Control intact (n=7), control OVX (n=7), IUGR intact (n=7), and IUGR OVX (n=8). *P<0.01 vs IUGR intact. All data are expressed as mean±SEM. (Used with permission, Figure 1, 144).

Figure 14

Effect of nicotine on angiotensin II (Ang II)–induced blood pressure (BP) response in sham, ovariectomy (OVX), and OVX+E₂ offspring. Diastolic BP (DBP), systolic BP (SBP), and mean arterial BP (MAP) responses to Ang II (10 µg/kg) were measured in sham, OVX, and OVX+E₂ groups of female offspring that had been exposed in utero to saline control or nicotine. All of the data are expressed as means±SEM from 6 animals in each group. †P<0.05 vs saline group; *P<0.05 vs data points in saline group. (Used with permission, Figure 1, 251).

Figure 15

Percentage (SE) post-menopausal by age 44–45 years by birthweight. (Used with permission, Figure 2, 215).

Figure 16

The effect of renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibition in adult male IUGR offspring. The ACE inhibitor enalapril was administrated at a dose of 250 mg/l via drinking water for 2 wk starting at 14 wk of age in IUGR offspring. MAP was measured by radio telemetry from 12 to 16 wk of age in conscious and free-moving animals that underwent either sham (intact) or castration (CTX) at 10 wk of age. IUGR intact untreated (n = 8), IUGR CTX untreated (n = 7), IUGR intact treated (n = 8), IUGR CTX treated (n = 8). *P < 0.05 vs. IUGR intact, †P < 0.05 vs. IUGR intact; and ‡P < 0.05 vs. IUGR CTX. All data are expressed as means ± SE. (Used with permission, Figure 2, 145).

Figure 17

Renal ACE and ACE2 mRNA expression in intact and ovariectomized control and IUGR offspring. Renal ACE and ACE2 mRNA expressions were assessed using real-time PCR. Results were calculated using the 2^−ΔΔCT method and expressed in folds increase/decrease of the gene of interest; control-intact (n=7), IUGR-intact (n=7), control-OVX (n=7), and IUGR-OVX (n=8). *P<0.05 vs control-intact ACE2. †P<0.05 vs IUGR-intact ACE2. All of the data are expressed as mean±SEM. (Used with permission, Figure 5, 144).

Figure 18

Mean arterial pressure in female control and IUGR rats measured by (a) telemetry or (b) chronically instrumented catheters in the conscious state 2 weeks post bilateral renal denervation. *P<0.05, †P<0.01, ‡P<0.001. Data values represent mean±SE. (Used with permission, Figure 5, 84).

Figure 19

Effect of prenatal dexamethasone and renal denervation on type 3 Na⁺/H⁺ exchanger (NHE3) protein abundance. (Used with permission, Figure 3, 32).

Figure 20

Renal superoxide production and urinary excretion of F₂-isoprostanes in male and female control and intrauterine growth-restricted (IUGR) offspring treated with the superoxide dismutase (SOD) mimetic Tempol (1 mmol/L) or vehicle (tap water ad libitum) from 14 weeks to 16 weeks of age. A, 24-hour urinary excretion of F₂-isoprostane; B, Renal basal superoxide anion production; and C, Renal NADPH oxidase–dependent superoxide anion production. *P<0.05 vs untreated male control, #P<0.05 vs untreated male IUGR, †P<0.05 vs untreated male IUGR. Data values represent mean±SE. □, control; ■, IUGR. (Used with permission, Figure 3, 146).

Figure 21

Effect of antenatal nicotine on vascular malondialdehyde (MDA) and superoxide dismutase (SOD) activities. Pregnant rats were treated with saline (control) or nicotine, MDA (A) and SOD activity (B) were determined in aortas isolated from 5 months old male offspring. Data are means ± SEM of tissues from five animals. *P < 0.05 versus control. (Used with permission, Figure 4, 233).

Figure 22

A: renal tubular injury scores in response to a mild I/R in NBW and LBW rats untreated and treated with tempol. The degree of tubular injury was scored using an established method of semiquantitive evaluation of 10 fields randomly selected per each examined kidney (high-power fields). All data are expressed as means ± SE. *P < 0.005 vs. all other groups. †P < 0.05 vs. LBW untreated counterpart. B: microphotographs representing renal tubular injury in response to a mild I/R in NBW and LBW rats untreated and treated with tempol. a: NBW sham. b: LBW sham. c: NBW mild renal I/R. d: LBW mild renal I/R. e: NBW mild renal I/R + tempol. f: LBW mild renal I/R + tempol. (All pictures are hematoxylin and eosin at ×400 magnification. Scale bars = 50 µm.) (Used with permission, Figure 8, 143).

Figure 23

Schematic diagram of the fetal programming of cardiovascular risk that originates from adverse exposure to maternal insults during gestational life and programs alterations in structure and physiology that contribute to the development of increased cardiovascular risk in later life.