Therapeutic angiogenesis: Molecular chit chat

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Placental growth factor (PGF) modulates molecular crosstalk between the vascular endothelial growth factor (VEGF) binding receptor tyrosine kinases Flt1 and Flk1, with potential therapeutic implications.

Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) to treat cardiac ischemia and ischemic limbs is currently undergoing clinical trials. So far, the results are promising, but atherosclerosis or diabetes impair response to VEGF. For patients with these conditions, the therapy would be greatly enhanced if additional growth factors that increase the VEGF response were also used.

VEGF and its homolog placental growth factor (PGF) bind receptor tyrosine kinases (RTKs) as homo- or heterodimers. These RTKs then engage in intramolecular crosstalk by transphosphorylating via their juxtaposing kinase domains. The RTK Flt1 (also known as VEGFR1) binds to both VEGF and PGF, whereas the RTK Flk1 (also known as VEGFR2) binds to only VEGF. PGF is known to enhance VEGF-driven angiogenesis in ischemic tissues. In order to dissect interactions between these pathways further, Peter Carmeliet and colleagues have investigated the regulatory role that PGF plays in inter- and intramolecular crosstalk between VEGF regulated RTKs.

The authors examined how activation of Flt1 by PGF affected the VEGF/Flk1-driven apoptotic protection of capillary endothelial cells (CECs), and discovered that Flt1 transactivated Flk1 via an intermolecular reaction between the receptor homodimers. Using mass spectrometry, the authors revealed that even though VEGF and PGF both bind and activate Flt1, they do so by phosphorylating different tyrosine residues. The authors provide further insight into the activation mechanics of VEGF and PGF on Flt1 through microarray analysis to show that PGF-Flt1 activation switches on a downstream genetic profile distinct from that of VEGF-Flt1 activation, revealing a PGF-driven biological effect independent of VEGF-Flt1 signaling.

The presence of VEGF and PGF significantly increases the formation of Flk1/Flt1 heterodimers in CECs. It is this activation of RTK intramolecular heterodimer crosstalk by VEGF/PGF which stimulates angiogenesis. In a mouse model resistant to VEGF treatment, PGF alone was shown to be ineffective in inducing angiogenesis, however, when used in combination with VEGF, angiogenesis was increased relative to VEGF alone. Using a combination of VEGF and PGF in therapeutic angiogenesis could therefore greatly aid treatment in patients not currently responding to VEGF

Brenda Riley, Assistant Editor
Signaling Gateway

References

Autiero, M. Waltenberger, J. Communi, D. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nature Medicine, 9, 936–943 (2003) 10.1038/nm884