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

Abstract

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.

Microorganisms linked to inflammatory bowel disease-associated dysbiosis differentially impact host physiology in gnotobiotic mice

“…These genes are involved in angiogenesis stimulation and are upregulated during angiogenesis (Nichol and Stuhlmann, 2012;Rocha et al, 2014). The upregulation of these two genes was confirmed, with expression higher than that in conventionalized mice (Figure 9a).…”

“…These genes are involved in pro-angiogenic (Esm1, Vegfr2 and Tie2) or anti-angiogenic (CD36) processes (Febbraio et al, 2001;Roskoski, 2008;Cascone and Heymach, 2012;Rocha et al, 2014), and they were upregulated and/or present in the top upregulated expression signature as shown by the microarray assays performed on S. boulardii monocolonized mice. We observed that S. boulardii culture supernatant induced the expression of the four endothelial genes, when compared with the control medium (Figure 9d), confirming the modulation of angiogenesis and the maturation of blood vessels by the yeast.…”

VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions

“…Indeed, both pathways are required for neurite elongation but not for neurite formation or growth initiation. Additionally, we found other candidate genes that may be involved in VEGF signaling, such as Endothelial cell-specific molecule 1 (Esm1), which is a VEGF pathway mediator (24), and Apelin (Apln) a neuropeptide that acts as a neuroprotectant (25,26). Furthermore, we found that distinct ligands that bind the VEGF receptor (such as PlGF) or interact with similar intracellular mediators (i.e., HB-EGF) also induced neurite growth in TG neurons but with less potency than VEGF-B.…”

SoxF Transcription Factors Are Positive Feedback Regulators of VEGF Signaling

“…Thus, its activity should be carefully regulated to build a functional vascular network. 28,29 In general, multiple positive and negative feedback controls exist for the balanced regulation of various signaling pathways. A negative feedback system is essential for maintaining the homeostasis of signaling activity, whereas a positive feedback control can amplify a faint input signal for a greater output.…”