Objective— Studies of Tie1 gene-targeted embryos have demonstrated loss of blood vessel integrity, but the relevance of Tie1 in lymphatic vasculature development is unknown. We tested the hypothesis that the swelling observed in Tie1 mutant embryos is associated with lymphatic vascular defects.

Methods and Results— We could extend the survival of the Tie1-deficient embryos in the ICR background, which allowed us to study their lymphatic vessel development. At embryonic day (E) 14.5, the Tie1^−/− embryos had edema and hemorrhages and began to die. Immunohistochemical analysis revealed that they have abnormal lymph sacs. Tie1^−/− mutants were swollen already at E12.5 without signs of hemorrhage. Their lymph sacs were abnormally patterned, suggesting that lymphatic malformations precede the blood vascular defects. We generated mice with a conditional Cre/loxP Tie1^neo locus and found that the homozygous Tie1^neo/neo hypomorphic embryos survived until E15.5 with lymphatic malformations resembling those seen in the Tie1^−/− mutants.

Conclusion— Our data show that loss of Tie1 results in lymphatic vascular abnormalities that precede the blood vessel phenotype. These findings indicate that Tie1 is involved in lymphangiogenesis and suggest differential requirements for Tie1 signaling in the two vascular compartments.