Esm1 Modulates Endothelial Tip Cell Behavior and Vascular Permeability by Enhancing VEGF Bioavailability

• DOI: 10.1161/circresaha.115.304718
• Publication Date: 2014-07-24T07:00:27Z
• Authors: Susana F. Rocha; Maria Schiller; Ding Jing; Hang Li; Stefan Butz; Dietmar Vestweber; Daniel Biljes; Hannes C.A. Drexler; Melina Nieminen-K...; Peter Vajkoczy; Susanne Adams; Rui Benedito; Ralf H. Adams
• Keywords: Inflammation; Male; Mice, Knockout; Vascular Endothelial Growth Factor A; 0301 basic medicine; Cell Membrane Permeability; Cell Membrane; Biological Availability; Endothelial Cells; Neovascularization, Physiologic; Mice, Transgenic; Fibronectins; Mice; 03 medical and health sciences; Models, Animal; Animals; Proteoglycans; Signal Transduction

Rationale:

Endothelial cell–specific molecule 1 (Esm1) is a secreted protein thought to play a role in angiogenesis and inflammation. However, there is currently no direct in vivo evidence supporting a function of Esm1 in either of these processes.

Objective:

To determine the role of Esm1 in vivo and the underlying molecular mechanisms.

Methods and Results:

We generated and analyzed Esm1 knockout ( Esm1

KO

) mice to study its role in angiogenesis and inflammation. Esm1 expression is induced by the vascular endothelial growth factor A (VEGF-A) in endothelial tip cells of the mouse retina. Esm1

KO

mice showed delayed vascular outgrowth and reduced filopodia extension, which are both VEGF-A–dependent processes. Impairment of Esm1 function led to a decrease in phosphorylated Erk1/2 (extracellular-signal regulated kinases 1/2) in sprouting vessels. We also found that Esm1

KO

mice displayed a 40% decrease in leukocyte transmigration. Moreover, VEGF-induced vascular permeability was decreased by 30% in Esm1

KO

mice and specifically on stimulation with VEGF-A 165 but not VEGF-A 121 . Accordingly, cerebral edema attributable to ischemic stroke–induced vascular permeability was reduced by 50% in the absence of Esm1. Mechanistically, we show that Esm1 binds directly to fibronectin and thereby displaces fibronectin-bound VEGF-A 165 leading to increased bioavailability of VEGF-A 165 and subsequently enhanced levels of VEGF-A signaling.

Conclusions:

Esm1 is simultaneously a target and modulator of VEGF signaling in endothelial cells, playing a role in angiogenesis, inflammation, and vascular permeability, which might be of potential interest for therapeutic applications.