Increased collagen deposition in the heart of chronically hypoxic ovine fetuses

This study determined the effect of chronic intrauterine hypoxia on collagen deposition in the fetal sheep heart. Moderate or severe hypoxia was induced by placental embolization in chronically catheterized fetal sheep for 15 days starting at gestational day 116 ± 2 (term ∼147 days). The fetal right and left ventricle were evaluated for collagen content using a Sirius red dye and for changes in signaling components of pathways involved in collagen synthesis and remodeling using quantitative polymerase chain reaction and Western blot. In severely hypoxic fetuses (n = 6), there was a two-fold increase (P < 0.05) in the percentage staining for collagen in the right ventricle, compared with control (n = 6), whereas collagen content was not altered in the moderate group (n = 4). Procollagen I and III mRNA levels were increased in the right ventricle, two-fold (P < 0.05) and three-fold (P < 0.05), respectively, in the severe group relative to control. These changes were paralleled by a two-fold increase (P < 0.05) in mRNA levels of the pro-fibrotic cytokine, transforming growth factor β (TGF-β1), in the right ventricle. In the right ventricle, the mRNA levels of matrix metalloproteinase 2 (MMP-2) and its activator, membrane-type MMP (MTI-MMP) were increased five-fold (P = 0.06) and three-fold (P < 0.05), respectively, relative to control. Protein levels of TGF-β were increased in the left ventricle (P < 0.05). Thus, up-regulated collagen synthesis leading to increased collagen content occurs in the chronically hypoxic fetal heart and may contribute to the right ventricular diastolic and systolic dysfunction reported in human intrauterine growth restriction fetuses.