The Epidermal Growth Factor-like Domain of CD93 Is a Potent Angiogenic Factor

Abstract

Human CD93, an epidermal growth factor (EGF)-like domain containing transmembrane protein, is predominantly expressed in the vascular endothelium. Studies have shown that AA4, the homolog of CD93 in mice, may mediate cell migration and angiogenesis in endothelial cells. Soluble CD93 has been detected in the plasma of healthy individuals. However, the role of soluble CD93 in the endothelium remains unclear. Recombinant soluble CD93 proteins with EGF-like domains (rCD93D123, with domains 1, 2, and 3; and rCD93D23, with domains 2 and 3) were generated to determine their functions in angiogenesis. We found that rCD93D23 was more potent than rCD93D123 in stimulating the proliferation and migration of human umbilical vein endothelial cells (HUVECs). Production of matrix-metalloproteinase 2 increased after the HUVECs were treated with rCD93D23. Further, in a tube formation assay, rCD93D23 induced cell differentiation of HUVECs through phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase and extracellular signal-regulated kinases-1/2 signaling. Moreover, rCD93D23 promoted blood vessel formation in a Matrigel-plug assay and an oxygen-induced retinopathy model in vivo. Our findings suggest that the soluble EGF-like domain containing CD93 protein is a novel angiogenic factor acting on the endothelium.

Elevated Expression of the C-Type Lectin CD93 in the Glioblastoma Vasculature Regulates Cytoskeletal Rearrangements That Enhance Vessel Function and Reduce Host Survival

“…Consistent with a role for CD93 in angiogenesis, a recombinant protein containing the EGF-like domain and the serine-threonine-rich mucin-like domain of CD93 has been demonstrated to have proangiogenic properties, but the effects were moderate and less evident in total sCD93 where the CTLD is included (16). Moreover, an antibody recognizing the extracellular domain of CD93 is able to inhibit proliferation, migration, and sprouting of human endothelial cells (17).…”

Molecular characterization and expression analysis of mouse epidermal growth factor-like domain 8

“…The EGFL domain of each protein has diverse physiological functions. For instance, the EGFL domain of CD93 has a central role in eliciting angiogenesis by stimulating proliferation, migration and in vitro tube formation of human umbilical vein endothelial cells (3). The EGFLs in thrombospondins induce synaptogenesis by interacting with neuronal cell-surface receptors such as α2δ-1 (4).…”

The Great Escape; the Hallmarks of Resistance to Antiangiogenic Therapy

“…In addition, several members of the galectin protein family have been found Hallmarks of Resistance to Antiangiogenic Therapy to induce and facilitate angiogenesis . Other recent additions to the growing list of angiostimulatory growth factors and receptors include angiopoietin-like 7 (Parri et al, 2014), high-mobility group box 1 (van Beijnum et al, 2013), metabotropic glutamate receptor-1 (Speyer et al, 2014), soluble CD93 (Kao et al, 2012), and prograstin (Najib et al, 2014).…”