Low-level basal vascular permeability (BVP) provides nutrients to normal tissues, and increased vascular permeability is characteristic of inflammation and cancer. We recently reported that VEGF-A, a potent vascular permeabilizing and angiogenic factor, exerts much of its angiogenic activity by up-regulating expression of TR3/ Nur77, an orphan nuclear transcription factor, in vascular endothelial cells (EC). To determine whether TR3/Nur77 had a more general role in regulating vascular permeability, we found that histamine, serotonin, and platelet-activating factor, small molecule vascular permeabilizing agents, also increased TR3/Nur77 expression acutely in EC. BVP and the acute vascular hyperpermeability (AVH) induced by these vascular permeabilizing factors were greatly decreased in Nur77 −/− mice, and both BVP and AVH correlated with Nur77 expression levels in several different mouse strains. BVP and AVH were enhanced in transgenic mice in which Nur77 was selectively overexpressed in vascular EC, whereas both were suppressed in mice overexpressing dominant-negative Nur77. Chronic vascular hyperpermeability (CVH) was induced long before the onset of angiogenesis in a modified, in vivo Matrigel assay that included PT67 cells packaging retroviruses expressing Nur77-sense, whereas inclusion of cells packaging viruses expressing Nur77-antisense prevented VEGF-A-induced CVH. TR3/ Nur77 modulated vascular permeability by increasing endothelial nitric-oxide synthase expression and by downregulating several EC junction proteins that maintain vascular homeostasis. Both functions required TR3/Nur77 transcriptional activity. Taking these data together, TR3/Nur77 is up-regulated by several vascular permeabilizing agents and has critical roles in mediating BVP, AVH, and CVH.

Phosphoinositide 3-kinase (PI3K) is activated by transmembrane tyrosine kinases such as vascular endothelial growth factor (VEGF) receptors and Tie2 (tunica intima endothelial kinase 2), both of which are key regulators of vascular development. However, the in vivo role of PI3K during developmental vascularization remains to be defined. Here we demonstrate that mice deficient in the p110␣ catalytic subunit of PI3K display multiple vascular defects, including dilated vessels in the head, reduced branching morphogenesis in the endocardium, lack of hierarchical order of large and small branches in the yolk sac, and impaired development of anterior cardinal veins. These vascular defects are strikingly similar to those in mice defective in the Tie2 signaling pathway. Indeed, Tie2 protein levels were significantly lower in p110␣-deficient mice.

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Mice carrying a homozygous germ-line mutation in the nm23-M1 gene that eliminates its protein expression and drives expression of beta-galactosidase by nm23-M1 promoter have been generated. nm23-M1 gene inactivation is not teratogenic and the pups can grow to adult age without apparent health problems. However, they undergo a growth retardation and knocked out females cannot feed their pups. Both effects are background dependent. Beta-galactosidase mapping of nm23-M1 promoter activation during embryogenesis shows that the nm23-M1 gene is principally expressed in epithelial layer of tissues which require inductive epithelial-mesenchymal interactions for their formation. In conclusion, invalidated mice could be interesting models to analyze the role of nm23-M1 on signal transduction pathway regulation, or cancer induction and proliferation.