Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an Nethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.

Abstract-Preeclampsia is associated with impaired uteroplacental adaptations during pregnancy and abnormalities in the endothelial NO synthase (eNOS)-NO pathway, but whether eNOS deficiency plays a causal role is unknown. Thus, the objective of the current study was to determine the role of eNOS in the mother and/or conceptus in uteroplacental changes during pregnancy using eNOS knockout mice. We quantified uterine artery blood flow using microultrasound, visualized the uteroplacental vasculature using vascular corrosion casts, and used pimonidazole and hypoxia-inducible factor 1␣ immunohistochemistry as markers of hypoxia in the placentas of eNOS knockout mice versus the background strain, C57Bl/6J (wild type). We found that increases in uteroplacental blood flow, uterine artery diameter, and spiral artery length were reduced, and markers of placental hypoxia in the junctional zone were elevated in late gestation in eNOS knockout mice. Both maternal and conceptus genotypes contributed to changes in uterine artery diameter and flow. Despite placental hypoxia, placental soluble fms-like tyrosine kinase 1 and tumor necrosis factor-␣ mRNA, and in maternal plasma, soluble fms-like tyrosine kinase 1 were not elevated in eNOS knockout mice. Thus, our results show that both eNOS in the mother and the conceptus contribute to uteroplacental vascular changes and increased uterine arterial blood flow in normal pregnancy. Key Words: preeclampsia/pregnancy Ⅲ blood flow regulation Ⅲ NO Ⅲ hypoxia Ⅲ placenta Ⅲ endothelial NO synthase T he maternal cardiovascular system undergoes structural and functional changes to accommodate the increased circulatory requirements of the growing fetus. Nowhere is this more profound than in the uteroplacental vasculature, where a marked increase in uteroplacental blood flow is achieved by a large reduction in vascular resistance 1,2 and pronounced enlargement and structural reorganization of the uterine and spiral arteries.3 Failure to make or to sustain these changes may result in preeclampsia, one of the most common and serious complications of human pregnancy.The mechanisms mediating uteroplacental changes during pregnancy are not fully understood. However, the L-arginine-NO pathway appears to play a central role in both normal pregnancy and in preeclampsia. 4 In preeclampsia in humans, diverse elements of the l-arginine-NO signaling pathway may be abnormal, including reduced l-arginine substrate or cofactor availability, reduced endothelial NO synthase (eNOS) enzyme activity attributed to gene polymorphisms, or elevated levels of asymmetrical dimethylarginine. 4 In pregnant rats 5 and mice, 6 NO synthase inhibition with N G -nitro-L-arginine methyl ester induces preeclamptic signs.Despite considerable evidence implicating eNOS in preeclampsia, eNOS knockout (KO) mice do not develop the hallmark signs, gestational hypertension 7-9 or proteinuria. 9Indeed, arterial pressure in eNOS KO mice decreases during pregnancy to become similar to that of pregnant wild-type controls. 7-9 Nevertheless, t...