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The placental labyrinth is the interface for gas and nutrient exchange between the embryo and the mother; hence its proper development is essential for embryogenesis. However, the molecular mechanism underlying development of the placental labyrinth, particularly in terms of its endothelial organization, is not well understood. Here, we determined that fibronectin leucine-rich transmembrane protein 2 (FLRT2), a repulsive ligand of the UNC5 receptor family for neurons, is unexpectedly expressed in endothelial cells specifically in the placental labyrinth. Mice lacking FLRT2 in endothelial cells exhibited embryonic lethality at mid-gestation, with systemic congestion and hypoxia. Although they lacked apparent deformities in the embryonic vasculature and heart, the placental labyrinths of these embryos exhibited aberrant alignment of endothelial cells, which disturbed the feto-maternal circulation. Interestingly, this vascular deformity was related to endothelial repulsion through binding to the UNC5B receptor. Our results suggest that the proper organization of the placental labyrinth depends on coordinated inter-endothelial repulsion, which prevents uncontrolled layering of the endothelium. [ABSTRACT FROM AUTHOR]

Hemorrhagic stroke is a significant cause of morbidity and mortality in children, and is frequently associated with intracranial vascular malformations. One prevalent form of these vascular malformations, cerebral cavernous malformation, is characterized by thin-walled vascular cavities that hemorrhage and has been linked to loss-of-function mutations in CCM1. The neural and epithelial expression of CCM1 in adulthood suggests that cavernous malformations may be the result of primary neural defects. In this study, we generated mice lacking Ccm1 and demonstrate that Ccm1 is ubiquitously expressed early in embryogenesis and is essential for vascular development. Homozygous mutant embryos die in mid-gestation and the first detectable defects are exclusively vascular in nature. The precursor vessels of the brain become dilated starting at E8.5, reminiscent of the intracranial vascular defects observed in the human disease. In addition, there is marked enlargement and increased endothelial proliferation of the caudal dorsal aorta, as well as variable narrowing of the branchial arch arteries and proximal dorsal aorta. These vascular defects are not secondary to primary neural defects, as neural morphology and marker expression are normal even subsequent to the onset of vascular pathology. The defects in the vascular structure of embryos lacking Ccm1 are associated with early downregulation of artery-specific markers, including the Efnb2- and Notch-related genes. Finally, consistent with the murine data, we found that there is an analogous reduction in Notch gene expression in arterioles from humans with mutations in CCM1. Our studies suggest that cavernous malformations result from primary vascular rather than neural defects. [ABSTRACT FROM AUTHOR]

There is emerging evidence that the canonical neural guidance factor netrin can also direct the growth of blood vessels. We deleted the gene encoding UNC5B, a receptor for the netrin family of guidance molecules, specifically within the embryonic endothelium of mice. The result is a profound structural and functional deficiency in the arterioles of the placental labyrinth, which leads first to flow reversal in the umbilical artery and ultimately to embryonic death. As this is the only detectable site of vascular abnormality in the mutant embryos, and because the phenotype cannot be rescued by a wild-type trophectoderm, we propose that UNC5B-mediated signaling is a specific and autonomous component of fetal-placental angiogenesis. Disruption of UNC5B represents a unique example of a mutation that acts solely within the fetal-placental vasculature and one that faithfully recapitulates the structural and physiological characteristics of clinical uteroplacental insufficiency. This pro-angiogenic, but spatially restricted requirement for UNC5B is not unique to murine development, as the knock-down of the Unc5b ortholog in zebrafish similarly results in the specific and highly penetrant absence of the parachordal vessel, the precursor to the lymphatic system. [ABSTRACT FROM AUTHOR]