Esm1 Modulates Endothelial Tip Cell Behavior and Vascular Permeability by Enhancing VEGF Bioavailability
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 analysed Esm1 knockout (Esm1KO) 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. Esm1KO 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 in sprouting vessels. We also found that Esm1KO mice displayed a 40% decrease in leukocyte transmigration. Moreover, VEGF-induced vascular permeability was decreased by 30% in Esm1KO mice, and specifically upon stimulation with VEGF-A165 but not VEGF-A121. Accordingly, cerebral edema due 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-A165 leading to increased bioavailability of VEGF-A165 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.
- vascular endothelial growth factor
- vascular inflammation
- vascular permeability
- cancer and stroke
- Received July 2, 2014.
- Revision received July 15, 2014.
- Accepted July 23, 2014.