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EMBRYONIC STEM CELLS

Lentiviral Rescue of Vascular Endothelial Growth Factor Receptor-2 Expression in Flk1–/– Embryonic Stem Cells Shows Early Priming of Endothelial Precursors

^aRudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden;
^bDepartment of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden;
^cInstitute of Pathology, Technische Universität Dresden-Faculty of Medicine "Carl Gustav Carus," Dresden, Germany

Key Words. Vascular endothelial growth factor receptor-2 • Flk1 • Vascular endothelial growth factor • Stem cells • Embryoid bodies Differentiation • Endothelial cells • Angiogenesis

Correspondence: Lena Claesson-Welsh, Ph.D., Rudbeck Laboratory, Department Genetics and Pathology, Uppsala University, Dag Hammarskjöldsv. 20, 751 85 Uppsala, Sweden. Telephone: 46-18-471-4363; Fax: 46-18-55-89-31; e-mail: Lena.Welsh{at}genpat.uu.se

Received May 22, 2007; accepted for publication July 31, 2007.
First published online in STEM CELLS EXPRESS   August 16, 2007.



The vascular endothelial growth factor (VEGF) family and its receptors are important for vascular development and maintenance of blood vessels, as well as for angiogenesis, the formation of new vessels. Loss of VEGF receptor-2 (VEGFR-2; designated Flk-1 in mouse) results in arrest of vascular and hematopoietic development in vivo. We used lentiviral transduction to reconstitute VEGFR-2 expression in flk1–/– embryonic stem (ES) cells. VEGF-induced vasculogenesis and sprouting angiogenesis were rescued in transduced ES cultures differentiating in vitro as EBs. Although the transgene was expressed in the pluripotent stem cells and lacked linage restriction during differentiation, the extent of endothelial recruitment was similar to that in wild-type EBs. Reconstitution of VEGFR-2 in flk1–/– ES cells allowed only precommitted precursors to differentiate into functional endothelial cells able to organize into vascular structures. Chimeric EB cultures composed of wild-type ES cells mixed with flk1–/– ES cells or reconstituted VEGFR-2-expressing ES cells were created. In the chimeric cultures, flk1–/– endothelial precursors were excluded from wild-type vessel structures, whereas reconstituted VEGFR-2-expressing precursors became integrated together with wild-type endothelial cells to form chimeric vessels. We conclude that maturation of endothelial precursors, as well as organization into vascular structures, requires expression of VEGFR-2.

Disclosure of potential conflicts of interest is found at the end of this article.

This article has been cited by other articles:

				H. Kawamura, X. Li, S. J. Harper, D. O. Bates, and L. Claesson-Welsh Vascular Endothelial Growth Factor (VEGF)-A165b Is a Weak In vitro Agonist for VEGF Receptor-2 Due to Lack of Coreceptor Binding and Deficient Regulation of Kinase Activity Cancer Res., June 15, 2008; 68(12): 4683 - 4692. [Abstract] [Full Text] [PDF]