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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2142.)
© 2007 American Heart Association, Inc.

Vascular Biology

Platelet-Derived Growth Factor Receptor-β Constitutive Activity Promotes Angiogenesis In Vivo and In Vitro

Peetra U. Magnusson; Camilla Looman; Aive Åhgren; Yan Wu; Lena Claesson-Welsh; Rainer L. Heuchel

From the Department of Genetics and Pathology, Rudbeck Laboratory (P.U.M., L.C.-W.), and Ludwig Institute for Cancer Research (C.L., A.A., R.L.H.), Uppsala University, Uppsala, Sweden; Department of Experimental Therapeutics (Y.W.), ImClone Systems Incorporated, New York, NY.

Correspondence to Rainer L. Heuchel, Ludwig Institute for Cancer Research, Uppsala University, BMC, Box 595, 751 24 Uppsala, Sweden. E-mail Rainer.Heuchel{at}LICR.uu.se

Objective— Knockout studies have demonstrated crucial roles for the platelet-derived growth factor-B and its cognate receptor, platelet-derived growth factor receptor-β (PDGFR-β), in blood vessel maturation, that is, the coverage of newly formed vessels with mural cells/pericytes. This study describes the consequences of a constitutively activating mutation of the PDGFR-β (Pdgfrb^D849V) introduced into embryonic stem cells with respect to vasculogenesis/angiogenesis in vitro and in vivo.

Methods and Results— Embryonic stem cells were induced to either form teratomas in vivo or embryoid bodies, an in vitro model for mouse embryogenesis. Western blotting studies on embryoid bodies showed that expression of a single allele of the mutant Pdgfrb led to increased levels of PDGFR-β tyrosine phosphorylation and augmented downstream signal transduction. This was accompanied by enhanced vascular development, followed by exaggerated angiogenic sprouting with abundant pericyte coating as shown by immunohistochemistry/immunofluorescence. Pdgfrb^D849V/+ embryoid bodies were characterized by increased expression of vascular endothelial growth factor (VEGF)-A and VEGF receptor-2; neutralizing antibodies against VEGF-A/VEGF receptor-2 blocked vasculogenesis and angiogenesis in mutant embryoid bodies. Moreover, Pdgfrb^D849V/+ embryonic stem cell–derived teratomas in nude mice were more densely vascularized than wild-type teratomas.

Conclusion— Increased PDGFR-β kinase activity is associated with elevated expression of VEGF-A and VEGF receptor-2, acting directly on endothelial cells and resulting in increased vessel formation.

Embryonic stem cells carrying a knock-in for an activating mutation in the platelet-derived growth factor receptor-beta are characterized by significantly elevated ligand-independent receptor phosphorylation and downstream signaling. This results in increased vasculogenesis and angiogenesis in an in vitro differentiation system as well as in vivo forming teratomas.

Key Words: PDGF • PDGF receptor • signal transduction • embryonic stem cells • endothelial cells • vasculogenesis • angiogenesis

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