SUMMARY:Intrauterine growth restriction is associated with increased perinatal morbidity and mortality as well as with lifelong cardiovascular and metabolic complications. Deficiency of heme oxygenase 1 (HO-1) is associated with growth restriction in mice and in humans, suggesting a role for HO-1 in fetal growth and maintenance of pregnancy. We hypothesized that modulation of HO-1 in the pregnant rat would alter fetal growth. In pregnant dams, placental HO activity was significantly inhibited with zinc deuteroporphyrin IX 2,4 bis glycol, and HO-1 protein was increased by transducing adenoviral human HO-1. Inhibition of HO-1 by zinc deuteroporphyrin IX 2,4 bis glycol resulted in a significant decrease in pup size, whereas transfection with hHO-1 resulted in increased pup size. Furthermore, the expression of IGF binding protein-1 and its receptor paralleled the expression of HO-1 in the placenta and were significantly modulated by modification of HO-1 along with the expression of vascular endothelial growth factor. These observations demonstrate that HO-1 modulates fetal growth by its effects on placental growth factors. (Lab Invest 2002, 82:687-692).
Intrauterine growth restriction (IUGR) is defined as a birth weight below the 10th percentile for gestational age (Goldenberg et al, 1989). In the United States, 8.6% of live births are growth-restricted (Hediger et al, 1998). Fetal growth in utero is influenced by extrinsic factors such as maternal vascular disease or intrinsic factors resulting from cell or organ dysfunction.Adverse effects of IUGR are seen immediately at birth, but the long-term morbidity and mortality of IUGR manifest into adulthood. A direct correlation between low birth weight and several adult onset diseases such as Syndrome X (hypertension, noninsulin-dependent diabetes mellitus, high serum triglycerides, and low serum high-density lipoproteins), cardiovascular diseases, and arterial hypertension has been demonstrated (Barker et al, 1993).The genetic contribution to IUGR is suggested by an increased prevalence of growth restriction in some families. A mutation in the IGF-1 gene can also cause IUGR (Woods et al, 1996). Furthermore, fetal cord serum IGF levels are increased in large-for-gestationage infants and decreased in IUGR infants (Giudice et al, 1995). However, this correlation is not universal (Wang et al, 1991). A family of binding proteins (BP) mediates the biologic actions of IGFs (Han et al, 1996). The type 1 IGF receptor (IGF-1R) is a transmembrane tyrosine kinase that is widely expressed in fetal tissues. Activation of the receptor after binding of IGF-1 or IGF-2 results in cell proliferation and protection from apoptosis (Granerus and Engstrom, 2001), suggesting an important pathway for intrauterine growth. In fact, targeted mutations of the IGF-1R gene reduce mouse embryonic growth (Accili et al, 1999). In contrast, IGF-BP binds to IGF-1 and inhibits its growthpromoting actions (Price et al, 1992;Woodall et al, 1996).Vascular endothelial growth factor (VEGF) can alter placen...
