Oxygen Sensing in the Ductus Arteriosus: Endothelin Still a Player

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Mouse aortic muscle cells respond to oxygen following cytochrome P450 3A13 gene transfer

We have previously shown that a cytochrome P450 (CYP450) hemoprotein from the 3A subfamily CYP3A13 for the mouse, serves as the sensor in the contraction of the ductus arteriosus in response to increased oxygen tension. In addition, we have identified endothelin-1 (ET-1) as the effector for this response. Here, we examined whether Cyp3a13 gene transfer confers oxygen sensitivity to cultured muscle cells from mouse aorta. Coincidentally, we determined whether the same hemoprotein is normally present in the vessel. Cyp3a13-transfected aortic cells responded to oxygen, whereas no significant response was seen in native cells or in cells transfected with an empty vector. Furthermore, this oxygen effect was curtailed by the ET-1/ETA receptor antagonist BQ-123. We also found that CYP3A13 occurs naturally in aortic tissue and its isolated muscle cells in culture. We conclude that CYP3A13 is involved in oxygen sensing, and its action in the transfected muscle cells of the aorta, as in the native cells of the ductus, takes place through a linkage to ET-1. However, the response of aortic muscle to oxygen, conceivably entailing the presence of CYP3A13 at some special site, is not seen in the native situation, and may instead unfold upon transfection of the parent gene

Compensatory Feto-Placental Upregulation of the Nitric Oxide System during Fetal Growth Restriction

Background: Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system. Methods: Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12). Results: Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric dimethylarginine decreased (p = 0.003). Nitrite rise coincided with an abnormal Doppler profile from umbilical arteries. Fetal growth restriction umbilical vein endothelial cells produced more nitrite and also exhibited reciprocal changes in vasodilator (upwards) and vasoconstrictor (downwards) transcripts. Elevation in blood nitrite and S-nitrosohemoglobin persisted postnatally in the fetal growth restriction offspring. Conclusion: Fetal growth restriction is typified by increased nitric oxide production during pregnancy and after birth. This response is viewed as an adaptative event to sustain placental blood flow. However, its occurrence may modify the endothelial phenotype and may ultimately represent an element of risk for cardiovascular disease in adult life.Fil: Pisaneschi, Silvia. Università degli Studi di Pisa; Italia. Scuola Superiore Sant’Anna; ItaliaFil: Strigini, Francesca A. L.. Università degli Studi di Pisa; ItaliaFil: Sanchez, Angel Matias. Università degli Studi di Pisa; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Begliuomini, Silvia. Università degli Studi di Pisa; ItaliaFil: Casarosa, Elena. Università degli Studi di Pisa; ItaliaFil: Ripoli, Andrea. National Research Council. Institute of Clinical Physiology, ; ItaliaFil: Ghirri, Paolo. Università degli Studi di Pisa; ItaliaFil: Boldrini, Antonio. Università degli Studi di Pisa; ItaliaFil: Fink, Bruno. Noxygen Science Transfer and Diagnostics; AlemaniaFil: Genazzani, Andrea R.. Università degli Studi di Pisa; ItaliaFil: Coceani, Flavio. Scuola Superiore Sant’Anna; ItaliaFil: Simoncini, Tommaso. Università degli Studi di Pisa; Itali

CD36 Deficiency Leads to Choroidal Involution via COX2 Down-Regulation in Rodents

Florian Sennelaub and colleagues show that CD36 deficiency leads to choroidal involution, a key feature of "dry" age-related macular degeneration, via COX-2 down-regulation in the retinal pigment epithelium