Ephrin-B2 Controls Cell Motility and Adhesion during Blood-Vessel-Wall Assembly

Abstract

New blood vessels are initially formed through the assembly or sprouting of endothelial cells, but the recruitment of supporting pericytes and vascular smooth muscle cells (mural cells) ensures the formation of a mature and stable vascular network. Defective mural-cell coverage is associated with the poorly organized and leaky vasculature seen in tumors or other human diseases. Here we report that mural cells require ephrin-B2, a ligand for Eph receptor tyrosine kinases, for normal association with small-diameter blood vessels (microvessels). Tissue-specific mutant mice display perinatal lethality; vascular defects in skin, lung, gastrointestinal tract, and kidney glomeruli; and abnormal migration of smooth muscle cells to lymphatic capillaries. Cultured ephrin-B2-deficient smooth muscle cells are defective in spreading, focal-adhesion formation, and polarized migration and show increased motility. Our results indicate that the role of ephrin-B2 and EphB receptors in these processes involves Crk-p130(CAS) signaling and suggest that ephrin-B2 has some cell-cell-contact-independent functions.

Cell–cell signaling via Eph receptors and ephrins

“…Defective mural-cell coverage is associated with the poorly organized and leaky vasculature seen in tumors or other human diseases. The authors further suggest that ephrin-B2 has some cell-cell-contactindependent functions [15] during these events.…”

“…In addition, EphB2 and ephrin-B2 mediate the interactions between the vessel endothelial cells and the adjacent mesenchymal cells [13,14]. An important new study [15] reveals that ephrin-B2 is also required for normal association between the blood-vessel endothelial cells and the supporting pericytes and vascular smooth muscle cells (mural cells). Defective mural-cell coverage is associated with the poorly organized and leaky vasculature seen in tumors or other human diseases.…”

Pdgfrb‐Cre targets lymphatic endothelial cells of both venous and non‐venous origins

“…Pdgfrb‐Cre mice (Foo et al ., 2006) were kindly provided by Ralf Adams (Max Planck Institute for Biomedicine, Münster, Germany). R26‐mTmG mice (Muzumdar et al ., 2007); obtained from the Jackson Laboratory) and Tie2‐Cre mice (Koni et al ., 2001) were described previously.…”

“…The Pdgfrb‐Cre line (Foo et al ., 2006), where Cre recombinase expression is driven by a transgenic fragment of the gene for platelet‐derived growth factor receptor β ( Pdgfrb ), has been used extensively to specifically target mural cells, namely vascular smooth muscle cells, pericytes and hepatic stellate cells; examples are given in ref (Abraham et al ., 2008; Foo et al ., 2006; Greif et al ., 2012; Henderson et al ., 2013; Jeansson et al ., 2011; Kogata et al ., 2009; Siegenthaler et al ., 2013; Stenzel et al ., 2009; Ye et al ., 2009; You et al ., 2014). We (Stanczuk et al ., 2015) and others (Klotz et al ., 2015) recently showed that Pdgfrb‐Cre unexpectedly also targets a large proportion of embryonic lymphatic endothelial cells (LECs) in the developing mesentery (Stanczuk et al ., 2015) and the heart (Klotz et al ., 2015).…”

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

“…Endothelial ephrinB2 can also interact with receptors on mural cells or perivascular mesenchyme to affect vascular development (Adams et al, 1999;Oike et al, 2002;Umeda et al, 2004). Finally, ephrinB2 on nonvascular cells can also affect vascular patterning (Zhang et al, 2001;Foo et al, 2006). Thus the outcome of ephrinB2-receptor signaling may depend on the cellular context and on the involvement of other signaling components, such as growth factor receptors (Pasquale, 2005;Zhang and Hughes, 2006).…”