ABSTRACT
Intrafetal insulin-like growth factor (IGF)-I promotes cardiac hypertrophy in the late-gestation fetal sheep; whether these effects are sustained is unknown. IGF-I was infused for 4 days at 80 microg/h from 121 to 125 days of gestation, and its effects at 128 days, 3 days after the infusion stopped, were determined by comparison with untreated fetal sheep. After IGF-I treatment, fetal weights were similar to those in control fetuses but kidney weights were bigger (P < 0.05), as were spleen weights of male fetuses (P < 0.05). Cardiac myocytes were larger in female than male fetal sheep (P < 0.001). IGF-I increased male (P < 0.001) but not female myocyte volumes. IGF-I did not alter the proportions of uni- or binucleated right or left ventricular myocytes. Female fetal sheep had a greater proportion of binucleated cardiac myocytes than males (P < 0.05). IGF-I-treated fetuses had a slightly greater proportion of right ventricular nuclei in cell cycle phase G(2)/M and a reduced proportion of G(0)/G(1) phase nuclei (P < 0.1). Therefore, evidence for IGF-I-stimulated cardiac cell hyperplasia in fetal sheep in late gestation was limited. In conclusion, the greater sizes and larger proportion of binucleated cardiac myocytes in female fetal sheep suggest that myocyte maturation may occur earlier in females than in males. This may explain in part the male sex-specific responsiveness of cardiac hypertrophy to IGF-I in late gestation. If IGF-I-stimulated cardiomyocyte growth is accompanied by maturation of contractile function, IGF-I may be a potential therapeutic agent for maintaining cardiac output in preterm males.
Subject(s)
Heart/anatomy & histology , Heart/embryology , Insulin-Like Growth Factor I/pharmacology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Sex Characteristics , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Carbon Dioxide/blood , Cardiac Output/drug effects , Cell Cycle/drug effects , Female , Gestational Age , Heart Rate/drug effects , Hydrogen-Ion Concentration/drug effects , Insulin-Like Growth Factor I/metabolism , Kidney/anatomy & histology , Kidney/embryology , Male , Organ Size/drug effects , Oxygen/blood , Pregnancy , Sheep , Spleen/anatomy & histology , Spleen/embryologyABSTRACT
Right (RVFW) and left (LVFW) ventricular free wall cardiac myocytes were collected from 25 fetal sheep aged 77-146 days gestation (term = 150 days gestation), six saline-infused catheterized fetal sheep (129 GD), and five lambs to measure gestational changes in uni- and binucleated cardiac myocyte numbers and cell volumes by confocal microscopy. At 77 days gestation, 2% of the myocytes were binucleated, which increased to 50% at 135 days gestation and 90% at 4-6 weeks after birth. RVFW uni- and binucleated myocytes were larger than those in the LVFW, and cell volumes of RVFW uni- and binucleated and LVFW binucleated myocytes (but not LVFW uninucleated myocytes) increased with gestation. Before birth, the approximate number of myocytes was greater in the LVFW than in the RVFW (P < 0.001). Before 110 GD, cardiac growth appeared to be due to myocyte hyperplasia, as approximate myocyte numbers and VFW weight increased at the same rate. After 110 days gestation, the approximate myocyte number/g VFW weight decreased, which suggests that myocyte hypertrophy, as well as hyperplasia, was occurring in association with the appearance of a greater proportion of binucleated cells after that time. By 4-6 weeks of age, there was marked hypertrophy of myocytes and an apparent reduction in myocyte number.
Subject(s)
Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Sheep/physiology , Animals , Animals, Newborn , Cell Count , Cell Nucleus , Cell Size , Female , Gestational Age , Heart/embryology , Heart/growth & development , Heart Ventricles/cytology , Heart Ventricles/embryology , Heart Ventricles/growth & development , Morphogenesis , Organ Size/physiology , PregnancyABSTRACT
Iodinated angiotensin II (Ang II) and its analogues are often assumed to have equal affinities for AT(1) and AT(2) receptor subtypes. However, using saturation and competition binding assays in several tissues from pregnant, nonpregnant, and fetal sheep, we found the affinity of 125I[Sar(1)Ile(8)] Ang II for Ang II receptors was different (P<0.05) between tissue types. The dissociation constants (Kd) and half maximal displacements of [Sar(1)Ile(8)] Ang II (Sar IC(50)) were directly related (P<0.05) to proportions of AT(1) receptors, and inversely related (P<0.05) to proportions of AT(2) receptors in tissues from all groups combined, in tissues from individual groups (pregnant, nonpregnant or fetal), and in some individual tissues (uterine arteries and aortae). This suggests that 125I[Sar(1)Ile(8)] Ang II has a different affinity for AT(1) and AT(2) receptors in ovine tissues. The Kds of 125I[Sar(1)Ile(8)] Ang II for "pure" populations of AT(1) and AT(2) receptors were 1.2 and 0.3 nM, respectively, i.e. affinity was four-fold higher for AT(2) receptors. We corrected the measured proportions of the receptor subtypes using their fractional occupancies. In tissues which contained at least 10% of each receptor subtype, the corrected proportions were significantly altered (P<0.05), even in some tissues, to the extent of being reversed.
