Resolution of Defective Dorsal Aortae Patterning in Sema3E-Deficient Mice Occurs Via Angiogenic Remodeling

Abstract

Background: Neuronal guidance cues influence endothelial cell (EC) behavior to shape the embryonic vascular system. The repulsive neuronal guidance cue, Semaphorin 3E (Sema3E), is critical for creating avascular zones that instruct and subsequently pattern the first embryonic vessels, the paired dorsal aortae (DA). Sema3E-/- embryos develop highly branched plexus-like vessels during vasculogenesis, instead of smooth paired vessels. Unexpectedly, despite these severe DA patterning defects, mutant mice are viable throughout adulthood. Results: Examination of Sema3E-/- mice reveals that the plexus-like DA resolve into single, unbranched vessels between embryonic day (E) E8.25 and E8.75. Although fusion of Sema3E-/- DA occurs slightly earlier than in heterozygotes, the DA are otherwise indistinguishable, suggesting a complete "rescue" in their development. Resolution of the DA null plexuses occurs by remodeling rather than by means of changes in cell proliferation or death. Conclusions: Normalization of Sema3E-/- DA patterning defects demonstrates resilience of embryonic vascular patterning programs. Additional repulsive guidance cues within the lateral plate mesoderm likely re-establish avascular zones lost in Sema3E-/- embryos and guide resolution of mutant plexus into branchless, parallel aortae. Our observations explain how Sema3E-/- mice survive throughout development and into adulthood, despite severe initial vascular defects. © 2013 Wiley Periodicals, Inc.