Research

Notch modulates VEGF action in endothelial cells by inducing Matrix Metalloprotease activity

Yasuhiro Funahashi^1,3, Carrie J Shawber³, Anshula Sharma³, Emi Kanamaru³, Yun K Choi³ and Jan Kitajewski^2,3*

• * Corresponding author: Jan Kitajewski jkk9@columbia.edu

Author Affiliations

¹ Tsukuba Research Laboratories, Eisai Co., Ltd, Ibaraki, Japan

² Pathology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, NY, NY 10032, USA

³ OB/GYN, Columbia University Medical Center, New York, NY 10032, USA

For all author emails, please log on.

Vascular Cell 2011, 3:2 doi:10.1186/2045-824X-3-2

Published: 18 January 2011

Abstract

Background

In the vasculature, Notch signaling functions as a downstream effecter of Vascular Endothelial Growth Factor (VEGF) signaling. VEGF regulates sprouting angiogenesis in part by inducing and activating matrix metalloproteases (MMPs). This study sought to determine if VEGF regulation of MMPs was mediated via Notch signaling and to determine how Notch regulation of MMPs influenced endothelial cell morphogenesis.

Methods and Results

We assessed the relationship between VEGF and Notch signaling in cultured human umbilical vein endothelial cells. Overexpression of VEGF-induced Notch4 and the Notch ligand, Dll4, activated Notch signaling, and altered endothelial cell morphology in a fashion similar to that induced by Notch activation. Expression of a secreted Notch antagonist (Notch1 decoy) suppressed VEGF-mediated activation of endothelial Notch signaling and endothelial morphogenesis. We demonstrate that Notch mediates VEGF-induced matrix metalloprotease activity via induction of MMP9 and MT1-MMP expression and activation of MMP2. Introduction of a MMP inhibitor blocked Notch-mediated endothelial morphogenesis. In mice, analysis of VEGF-induced dermal angiogenesis demonstrated that the Notch1 decoy reduced perivascular MMP9 expression.

Conclusions

Taken together, our data demonstrate that Notch signaling can act downstream of VEGF signaling to regulate endothelial cell morphogenesis via induction and activation of specific MMPs. In a murine model of VEGF-induced dermal angiogenesis, Notch inhibition led to reduced MMP9 expression.