Cross talk between the VEGF and Notch signalling pathways in endothelial cells


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Laura Harrington, Richard Sainson, Chern Ein Oon, Helen Sheldon, Ji-Liang Li, Adrian Harris

Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

Abstract

Cross talk between the VEGF and Notch signalling pathways in endothelial cells

VEGF is an established key regulator of physiological and pathological angiogenesis but recently the importance of the Notch signalling pathway has become clearer. Indeed the endothelial-specific Notch ligand, Dll4, like VEGF, is haploinsufficient and it is highly expressed in tumour vasculature. Our work and that of others has shown that these two signalling pathways interact. We have shown that xenograft tumours overexpressing Dll4 are resistant to anti-VEGF therapy and therefore understanding the cross talk between these two pathways is essential to derive the most benefit from anti-VEGF and anti-Notch anti-angiogenic therapies. To this end we have shown that VEGF stimulation induced Dll4 and Notch4 expression but not Jagged1 or Notch1 expression in HUVECs. Interestingly VEGF-induced Dll4 expression is γ-secretase-dependent while that of Notch4 is not. We are investigating this mechanism and have shown that VEGF stimulation of HUVECs led to rapid accumulation of Notch1ICD. Dll4 signalling led to downregulation of VEGFR2 and upregulation of VEGFR1 including the soluble form. This results in impairment of VEGF signal transduction indicating a negative feedback loop whereby VEGF upregulates Dll4 which in turn decreases the ability of HUVEC to respond to VEGF. Investigation of the complex relationship between these two pathways may help elucidate mechanisms of resistance to anti-VEGF therapy and suggest ways to better modulate these pathways to improve anti-angiogenic effects.