Altered Expression Patterns of EphrinB2 and EphB2 in Human Umbilical Vessels and Congenital Venous Malformations

Abstract

Vascular malformations cause discomfort and pain in children and are often associated with skeletal hypertrophy. Their molecular basis is poorly understood. Ephrin ligands and Eph receptor tyrosine kinases are involved in embryonic vascular development. In mice, some ephrin/Eph family members show a complementary expression pattern in blood vessels, with ephrinB2 being expressed on arterial and EphB4 on venous endothelium. Targeted deletions of the genes reveal their essential roles for conduit vessel development in mice, suggesting similar functions during human vascular development and deregulation in vascular malformations. Here, we have defined the expression patterns of human ephrinB2, EphB4, and EphB2 in normal vessels of neonates (i.e. umbilici) and adults and compared them with those in congenital venous malformations. In adults, normal vessels of the skin, muscle, and legs express ephrinB2 and EphB2 on arterial endothelial cells (ECs), whereas EphB4 is found in arteries and veins. In the umbilicus, EphB2 is a specific marker of arterial ECs, whereas ephrinB2 is additionally expressed in venous ECs, suggesting an arterial function of the veins. In venous malformations, the expression of EphB4 is not altered, but both ephrinB2 and EphB2 are ectopically expressed in venous ECs. This may reflect a nonphysiologic arterialization of malformed veins. Our study shows that the arterial markers ephrin B2 and EphB2 are expressed in a subset of veins, and it remains to be studied whether this is cause or consequence of an altered vascular identity. (Pediatr Res 57: 537-544, 2005) Abbreviations EC, endothelial cell SAM, sterile ␣ motif ␣-SMA, ␣-smooth muscle actin SMC, smooth muscle cell During embryogenesis, blood vessels form via two distinct processes, vasculogenesis and angiogenesis (1-5). Vasculogenesis involves the de novo development of endothelial cells (ECs) from mesodermal precursors, the angioblasts, and leads to the formation of the early vascular plexus. Later, blood vessels arise mainly from the preexisting ones by sprouting, splitting, and intussusceptive growth of capillaries in a process called angiogenesis. Remodeling of the primary vascular plexus into conduit vessels and capillaries ensures perfusion of all organs and tissues with blood. In the adult, angiogenesis accounts for neovascularization accompanying cyclic reproductive changes in women, as well as pathologic processes such as tumor growth, diabetic retinopathy, and rheumatoid arthritis (6,7).To date, three growth factor families have been identified as critical players of blood vessel development: vascular endothelial growth factors, angiopoietins, and ephrins (8,9). Unlike vascular endothelial growth factors and angiopoietins, which are secreted proteins, ephrins are attached to the plasma membrane and function in cell-cell communication (10). Ephrins can be divided into two subclasses: EphrinA ligands (ephrinA1-A5) are tethered to the outer cell surface via a glycosylphosphatidylinositol anchor, whereas ephrinB ligands (ephrinB1-B3) po...

Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes

“…Yet, much less is known about their roles in the adult vasculature. The arteriovenous asymmetrical expression patterns of ephrin-B2 and EphB4 are maintained in the adult (Diehl et al, 2005;Korff et al, 2006). Likewise, ephrin-B2 expression is prominently upregulated during adult neovascularization (Gale et al, 2001;Hayashi et al, 2005;Shin et al, 2001) and arteriogenic vessel remodeling (Korff et al, 2008).…”

EphB2 and EphB4 receptors forward signaling promotes SDF-1–induced endothelial cell chemotaxis and branching remodeling

“…9 After birth, EphB receptors and ephrin B ligands continue to be expressed by endothelial cells from various tissues; EphB2 and ephrin B2 display some selectivity for the arterial endothelium, whereas EphB4 is expressed in arterial and venous endothelium. 10 Functional assays in vitro have provided evidence that several EphB receptors and ephrin B ligands are active in human endothelial cells. Soluble dimeric forms of ephrin B ligands and EphB receptors, including Ephrin B1-Fc, ephrin B2-Fc, EphB4-Fc, and EphB1-Fc, promoted the growth, sprouting, migration, or assembly of capillary-like structures by various human endothelial cells, 6,[11][12][13][14][15][16] presumably by activating forward or reverse signaling.…”

Arterialization and anomalous vein wall remodeling in varicose veins is associated with upregulated FoxC2-Dll4 pathway

“…29 But another study by Diehl et al 28 reported that in low-flow venous malformations also arterialization can occur, probably due to turbulent blood flow rather than arterial shear stress or tangential stress. Our findings indicate that similar mechanisms could contribute to the morphological alterations in varicose veins as well.…”

“…EphrinB2 is, however, expressed solely in arterial endothelial cells even in adult human vessels. 28 We had reported earlier that ephrinB4 is downregulated in varicose veins. 6 Taking this cue, we assessed the expression pattern of ephrinB2 in our study specimens to look for any dysregulation in the ephrinB4/ephrinB2 axis in varicose veins.…”