Maternal nutrient restriction and the fetal left ventricle: decreased angiotensin receptor expression.

BACKGROUND: Adequate maternal nutrition during gestation is requisite for fetal nutrition and development. While a large group of epidemiological studies indicate poor fetal nutrition increases heart disease risk and mortality in later life, little work has focused on the effects of impaired maternal nutrition on fetal heart development. We have previously shown that 50% global nutrient restriction from 28-78 days of gestation (early to mid-pregnancy; term = 147 days) in sheep at mid-gestation retards fetal growth while protecting growth of heart and results in hypertensive male offspring at nine months of age. In the present study, we evaluate LV gene transcription using RNA protection assay and real-time reverse transcriptase polymerase chain reaction, and protein expression using western blot, of VEGF and AT1 and AT2 receptors for AngII at mid-gestation in fetuses from pregnant ewes fed either 100% (C) or 50% (NR) diet during early to mid-gestation. RESULTS: No difference between the NR (n = 6) and C (n = 6) groups was found in gene transcription of the AngII receptors. Immunoreactive AT1 (1918.4 +/- 154.2 vs. 3881.2 +/- 494.9; P < 0.01) and AT2 (1729.9 +/- 293.6 vs. 3043.3 +/- 373.2; P < 0.02) was decreased in the LV of NR fetuses compared to C fetuses. The LV of fetuses exposed to NR had greater transcription of mRNA for VEGF (5.42 +/- 0.85 vs. 3.05 +/- 0.19; P < 0.03) than respective C LV, while no change was observed in immunoreactive VEGF. CONCLUSION: The present study demonstrates that VEGF, AT1 and AT2 message and protein are not tightly coupled, pointing to post-transcriptional control points in the mid gestation NR fetus. The present data also suggest that the role of VEGF and the renin-angiotensin system receptors during conditions inducing protected cardiac growth is distinct from the role these proteins may play in normal fetal cardiac growth. The present findings may help explain epidemiological studies that indicate fetuses with low birth weight carry an increased risk of mortality from coronary and cardiovascular disease, particularly if these individuals have reduced cardiovascular reserve due to an epigenetic decrease in vascularization.

Maternal nutrient restriction in sheep: hypertension and decreased nephron number in offspring at 9 months of age.

Pregnant ewes were fed either a 50% nutrient-restricted (NR; n= 8) or a control 100% (C; n= 8) diet from day 28 to day 78 of gestation (dGA; term = 150 dGA). Lambs were born naturally, and fed to appetite throughout the study period. At 245 +/- 1 days postnatal age (DPNA), offspring were instrumented for blood pressure measurements, with tissue collection at 270 DPNA. Protein expression was assessed using Western blot, glomerulus number determined via acid maceration and hormone changes by radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). NR lambs had higher mean arterial pressure (MAP; 89.0 +/- 6.6 versus 73.4 +/- 1.6 mmHg; P < 0.05), fewer renal glomeruli (57.8 +/- 23.8 versus 64.6 +/- 19.3 x 10(4); P < 0.05), increased expression of angiotensin converting enzyme (ACE) in the renal cortex (942 +/- 130 versus 464 +/- 60 arbitrary pixel units (apu); P < 0.03), and increased angiotensin II receptor AT2 expression in the renal medulla (63.3 +/- 12.1 versus 19.5 +/- 44.2 x 10(4) apu; P < 0.03). All data are presented as mean +/-S.E.M. The present data indicate that global maternal nutrient restriction (50%) during early to mid-gestation impairs renal nephrogenesis, increases MAP, and alters expression of AT2 and ACE without an associated change in birth weight. These data demonstrate the existence of a critical window of fetal susceptibility during early to mid-gestation that alters kidney development and blood pressure regulation in later life.