Altered feto-placental vascularization, feto-placental malperfusion, and fetal growth restriction in mice with Egfl7 loss-of-function

Abstract

EGFL7 is a secreted angiogenic factor produced by embryonic endothelial cells. To understand its role in placental development, we established a novel <i>Egfl7</i> knockout mouse. The mutant mice have gross defects in chorioallantoic branching morphogenesis and placental vascular patterning. Microangiography and 3D imaging revealed patchy perfusion of <i>Egfl7^-/-</i> placentas marked by impeded blood conductance through sites of narrowed vessels. Consistent with poor feto-placental perfusion, <i>Egfl7</i> knockout resulted in reduced placental weight and fetal growth restriction. The placentas also showed abnormal fetal vessel patterning and over 50% reduction in fetal blood space. <i>In vitro</i>, placental endothelial cells were deficient in migration, cord formation and sprouting. Expression of genes involved in branching morphogenesis, <i>Gcm1</i>, <i>Syna</i> and <i>Synb</i>, and in patterning of the extracellular matrix, <i>Mmrn1</i>, were temporally dysregulated in the placentas. <i>Egfl7</i> knockout did not affect expression of the microRNA embedded within intron 7. Collectively, these data reveal that <i>Egfl7</i> is crucial for placental vascularization and embryonic growth, and may provide insight into etiological factors underlying placental pathologies associated with intrauterine growth restriction, which is a significant cause of infant morbidity and mortality.