Activation of the mitogen-activated protein kinases and Akt in response to pulmonary artery banding in the fetal sheep heart is developmentally regulated.

BACKGROUND

The postnatal heart responds to biomechanical stress with hypertrophy. The fetal heart may also undergo hyperplasia, but the percentage of mitotically active cardiomyocytes decreases throughout gestation. The signaling pathways controlling growth and proliferation in the fetal heart are poorly understood.

OBJECTIVE

To determine whether activation of the mitogen-activated protein kinases and Akt in the acute response to pressure loading in the fetal heart is developmentally regulated.

METHODS

Pulmonary artery banding (PAB) was performed in 100- or 128-day fetuses of twin gestation (n = 6 per group) for 6 h. One twin served as a control. Right ventricular (RV) and left ventricular (LV) mitogen-activated protein kinase, Akt, and cyclin D1 protein levels were determined by Western blot.

RESULTS

Within each gestational age group, hemodynamic and arterial blood gas values were similar between PAB and control fetuses. The total mitogen-activated protein kinase and Akt protein levels were unchanged by PAB at both gestational ages, as were active p38 and JNK levels. The RV levels of active ERK tended to decrease in 128-day PAB fetuses as compared with controls, and LV active ERK normalized to total ERK was significantly decreased. At gestational age (GA) 100 days, RV active ERK levels were significantly higher in PAB animals as compared with controls, with a trend towards increased active Akt levels. No differences were seen in the 100-day LV. The levels of the cell cycle promoter cyclin D1 were unchanged in all animals.

CONCLUSIONS

Pressure loading of the fetal sheep heart leads to developmentally regulated cell signaling profiles. ERK and possibly Akt may be important regulators of in vivo cardiomyocyte hyperplasia.