Endothelial cell–specific chemotaxis receptor (ecscr) promotes angioblast migration during vasculogenesis and enhances VEGF receptor sensitivity

Abstract

Endothelial cell-specific chemotaxis receptor (ECSCR) is a cell surface protein expressed by blood endothelial cells with roles in endothelial cell migration and signal transduction. We investigated the function of ecscr in the development of the zebrafish vasculature. Zebrafish ecscr is expressed in angioblasts and in axial vessels during angioblast migration and vasculogenesis. Morpholino-directed ecscr knockdown resulted in defective angioblast migration in the posterior lateral plate mesoderm, a process known to depend on vascular endothelial-derived growth factor (VEGF). In cultured cells, transfected ECSCR localized to actin-rich membrane protrusions, colocalizing with kinase insert domain protein receptor (KDR)/VEGF receptor 2 in these regions. ECSCR-silenced cells show reduced VEGF-induced phosphorylation of KDR but not of FMS-like tyrosine kinase 1 (FLT1)/VEGF receptor 1. Finally, chemical inhibition of VEGF receptor activity in zebrafish resulted in angioblast deficiencies that partially overlap with those seen in ecscr morphants. We propose that ecscr promotes migration of zebrafish angioblasts by enhancing endothelial kdr sensitivity to VEGF.

Endothelial Cell-specific Chemotaxis Receptor (ECSCR) Enhances Vascular Endothelial Growth Factor (VEGF) Receptor-2/Kinase Insert Domain Receptor (KDR) Activation and Promotes Proteolysis of Internalized KDR

“…16). For example, loss of ECSCR has resulted in differential impact on EC migration, depending on stimulus, cell type, and assay conditions (1,11,13,14). Our earlier (1) and current observations indicate that loss and gain of ECSCR can both result in decreased VEGF-dependent migration.…”

“…Infantile Hemangioma-Although the tissue distribution of ECSCR mRNA has been extensively characterized (1,11,14,25,26), the distribution of ECSCR protein in vivo is largely unknown. To investigate this and to identify the potential in vivo significance of the ECSCR-KDR interaction, we utilized our anti-ECSCR antiserum to screen a human cardiovascular disease tissue array for ECSCR protein expression (results presented in supplemental Table 1 and supplemental Fig.…”

Human endothelial stem/progenitor cells, angiogenic factors and vascular repair

“…The acute elevation of ECSM2 mRNA levels also correlated with the burn severity in terms of per cent total body surface area burnt in these human subjects (Fox et al 2008a). Interestingly, ECSM2, also known as endothelial cell-specific chemotaxis receptor (ECSCR), is an endothelial-restricted cell surface receptor that appears to enhance the sensitivity of VEGF in angioblasts during vasculogenesis (Verma et al 2010). Taken together, these results suggest that in response to burn injury and increased circulating VEGF and CXCL-12, both proangiogenic and endothelial cells (including late endothelial outgrowth cells) are rapidly mobilized into the peripheral blood.…”

Nogo-B receptor is essential for angiogenesis in zebrafish via Akt pathway

“…19 The zNgBR expression localizes in between somites ( Figure 1C) where endothelial cells are clearly observed in Tg(fli1a-nGFP) flat mounts ( Figure 1D). In comparison to other vascular genes such as Syx 22 and ESCR 23 that function in the developing vasculature, zNgBR follows the similar pattern of low to modest expression in ISVs. As shown in supplemental Figure 2D …”