Systemic Maternal Inflammation and Neonatal Hyperoxia Induces Remodeling and Left Ventricular Dysfunction in Mice

Abstract

AimsThe impact of the neonatal environment on the development of adult cardiovascular disease is poorly understood. Systemic maternal inflammation is linked to growth retardation, preterm birth, and maturation deficits in the developing fetus. Often preterm or small-for-gestational age infants require medical interventions such as oxygen therapy. The long-term pathological consequences of medical interventions on an immature physiology remain unknown. In the present study, we hypothesized that systemic maternal inflammation and neonatal hyperoxia exposure compromise cardiac structure, resulting in LV dysfunction during adulthood.Methods and ResultsPregnant C3H/HeN mice were injected on embryonic day 16 (E16) with LPS (80 µg/kg; i.p.) or saline. Offspring were placed in room air (RA) or 85% O2 for 14 days and subsequently maintained in RA. Cardiac echocardiography, cardiomyocyte contractility, and molecular analyses were performed. Echocardiography revealed persistent lower left ventricular fractional shortening with greater left ventricular end systolic diameter at 8 weeks in LPS/O2 than in saline/RA mice. Isolated cardiomyocytes from LPS/O2 mice had slower rates of contraction and relaxation, and a slower return to baseline length than cardiomyocytes isolated from saline/RA controls. α-/β-MHC ratio was increased and Connexin-43 levels decreased in LPS/O2 mice at 8 weeks. Nox4 was reduced between day 3 and 14 and capillary density was lower at 8 weeks of life in LPS/O2 mice.ConclusionThese results demonstrate that systemic maternal inflammation combined with neonatal hyperoxia exposure induces alterations in cardiac structure and function leading to cardiac failure in adulthood and supports the importance of the intrauterine and neonatal milieu on adult health.

Early life exposure to air pollution induces adult cardiac dysfunction

“…In a model of maternal inflammation induced by lipopolysaccharide injection, a cardiovascular phenotype was observed that was similar to what we found in mice exposed to both perinatal and in utero PM 2.5 exposure (42,43). Additionally, recent studies examining the placenta of pregnant mice exposed to PM 2.5 have shown altered morphology, such as reduced maternal blood space area as well as recruitment of inflammatory cells to the placental vasculature (44).…”

“…Cardiomyocytes were isolated as previously described (33,42,43,46,47). Briefly, hearts were removed and retrogradely perfused through the aorta with Liberase and trypsin until digested.…”

“…Isolated cells were then plated on laminin-coated glassbottom inserts (Cell MicroControls, Norfolk, VA) for functional analyses. Glass-bottom inserts were perfused with warm contractile buffer (27,33,42,43,46,47) within a flow chamber attached to an Olympus IX-71 microscope. Cells were stimulated (1 Hz, 3-ms duration) with a Myopacer Field-Stimulator system (IonOptix, Milton, MA), and functional properties of the cells were evaluated with the Sarclen Sarcomere Length Acquisition Module using the Myocam-S Digital CCD camera video imaging system (IonOptix).…”

Neonatal hyperoxia: effects on nephrogenesis and long-term glomerular structure

“…O2 and CO2 concentrations in the mouse housing chambers were continuously monitored (Servoflex MiniMP 5200; Servomex) for the duration of the hyperoxia exposure period; CO 2 concentrations did not rise throughout the exposure period. We used 65% O2 to avoid maternal and neonatal death through severe oxygen toxicity; this is a lower O2 concentration than has been used in other recent studies (32,38). All studies were approved by the Monash University Animal Ethics Committee and the treatment and care of animals conformed to the National Health and Medical Research Council of Australia's Code of Practice for the Care and Use of Animals for Scientific Purposes.…”

Preterm Birth and Hypertension Risk

“…92 A study on heart development found that in combination with maternal inflammation during gestation (commonly linked to preterm birth), postnatal hyperoxia exposure (85% O 2 from postnatal days 1 to 14) was associated with both structural remodeling and dysfunction of the left ventricle. 93 Certainly further studies are required to investigate completely the effect of hyperoxia exposure alone on renal and cardiac development.…”