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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4527-4535.
Prepublished online as a Blood First Edition Paper on February 24, 2004; DOI 10.1182/blood-2003-07-2315.
Submitted July 9, 2003
Accepted February 9, 2004
The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis
Joseph B Kearney, Nicholas C Kappas, Catharina Ellerstrom, Frank W DiPaola, and Victoria L Bautch*
Program in Genetics and Molecular Biology, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Program in Genetics and Molecular Biology, the University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Carolina Cardiovascular Biology Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
* Corresponding author; email: bautch{at}med.unc.edu.
Sprouting angiogenesis is critical to blood vessel formation, but the cellular and molecular controls of this process are poorly understood. We used time-lapse imaging of GFP-expressing vessels derived from stem cells to analyze dynamic aspects of vascular sprout formation, and to determine how the VEGF receptor flt-1 affects sprouting. Surprisingly, loss of flt-1 led to decreased sprout formation and migration, which resulted in reduced vascular branching. This phenotype was also seen in vivo, as flt-1-/- embryos had defective sprouting from the dorsal aorta. We previously showed that loss of flt-1 increases the rate of endothelial cell division. However, the timing of division vs. morphogenetic effects suggested that these two phenotypes were not causally linked, and in fact mitoses were prevalent in the sprout field of both wild-type and flt-1-/- mutant vessels. Rather, rescue of the branching defect by an sflt-1 transgene supports a model whereby flt-1 normally positively regulates sprout formation by production of sflt-1, a soluble form of the receptor that antagonizes VEGF signaling. Thus precise levels of bioactive VEGF-A and perhaps spatial localization of the VEGF signal are likely modulated by flt-1 to ensure proper sprout formation during blood vessel formation.
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