Vascular Endothelial Growth Factor A (VEGF-A) Is Involved in Guidance of VEGF Receptor-Positive Cells to the Anterior Portion of Early Embryos

Abstract

The hemangioblast in the mesoderm gives rise to both angioblasts and hematopoietic stem cells. The movement of hemangioblast precursor cells in the fetal trunk is a critical event in early embryogenesis. Vascular endothelial growth factor (VEGF) signaling is likely involved in this migration given the partial disturbance of VEGF receptor (VEGFR)-positive cell accumulation and migration in VEGFR2 null mice or mice with a truncated VEGFR1. However, it is not clear how the VEGF system regulates this migration or its direction. We show here that the expression of VEGF-A is dominant in the anterior portion of the embryo, whereas VEGFR1 and VEGFR2 are expressed in the posterior portion of the embryo. An inhibitor of VEGFR kinase blocked the migration of VEGFR-positive cells in a whole-embryo culture system. In addition, VEGFR-positive cells migrated toward a VEGFR1- or VEGFR2-specific ligand in vitro. Furthermore, VEGFR-positive cells derived from wild-type or VEGFR2^+/− mice moved rapidly anteriorly, whereas cells derived from VEGFR2^+/− mice carrying a truncated VEGFR1 [VEGFR1(TM-TK)^−/−] migrated little when injected into wild-type mice. These results suggest that the VEGF-A protein concentrated in the anterior region plays an important role in the guidance of VEGFR-positive cells from the posterior portion to the head region by interacting with VEGFR in the mouse embryo.

ACKNOWLEDGMENTS

We thank Tetsuo Noda (Cancer Institute) for the preparation of VEGFR1(TK)^−/− mice and Nobuaki Yoshida (University of Tokyo) for support with the transplantation technique.

This work was supported by Special Project Research on Cancer-Bioscience grant-in-aid 12215024 from the Ministry of Education, Culture, Sports, Science and Technology in Japan, by the program Research for the Future of the Japan Society for Promotion of Science, and by the program Promotion of Fundamental Research in Health Sciences from the Organization for Pharmaceutical Safety and Research.