Amanda Feigel

Eph-B4 prevents venous adaptive remodeling in the adult arterial environment

Stimulation of Eph-B4 prevents adaptive remodeling and preserves venous identity when veins are surgically placed into an arterial environment.

Reduced adult endothelial cell EphB4 function promotes venous remodeling

Reduced EphB4 expression is observed during vein graft adaptation and is associated with increased venous wall thickening. These findings suggest that EphB4 may mediate normal adult venous endothelial cell (EC) function and vein graft adaptation. We therefore tested the functional significance of EphB4 using EC with genetically reduced EphB4 signaling. EC were isolated from EphB4(+/+) and EphB4(+/-) mice. In vitro function was assessed through EC proliferation, migration, nitric oxide (NO) synthesis, and chemokine production. A mouse vein graft model was used to correlate in vitro findings with in vivo vein grafts. Smooth muscle cells (SMC) were subjected to proliferation and migration assays using EphB4(+/+) and EphB4(+/-) EC-conditioned medium. EphB4(+/-) EC exhibited diminished proliferation (P < 0.0001, n = 6), migration (P < 0.0001, n = 3), and NO production (P = 0.0012, n = 3). EphB4(+/-) EC had increased VEGF-A mRNA (P = 0.0006, n = 6) and protein (P = 0.0106, n = 3) as well as increased secretion of VEGF-A (P = 0.0010, n = 5), PDGF-BB (P < 0.0001, n = 6), and TGF-β1 (P < 0.0001, n = 6). EphB4(+/-)-conditioned medium promoted SMC proliferation (P < 0.0001, n = 7) and migration (P = 0.0358, n = 3). Vein grafts and EphB4(+/-) EC showed similarity with regard to VEGF-A and eNOS mRNA and protein expression. In conclusion, reduced venous EC EphB4 function is associated with a proangiogenic and mitogenic phenotype. EphB4(+/-) EC have increased secretion of SMC mitogens and reduced NO production that correlate with the thickened neointima formed during vein graft adaptation. These findings suggest that EphB4 remains active in adult venous EC and that loss of EphB4 plays a role in vein graft adaptation.

Venous and arterial identity: a role for caveolae?

Venous and arterial identity is predetermined in the embryo, with embryonic vessels expressing Eph-B4 differentiating into veins and vessels expressing ephrin-B2 differentiating into arteries. The specialized membrane organelles lipid rafts and caveolae serve as localized domains for proteins to interact with one another and play a role in signal transduction and vesicular trafficking. Several tyrosine kinase membrane receptors, including Eph-B1, have been colocalized to caveolae. These data suggest that caveolae and Eph receptors may have coordinated roles in determining vessel identity, not only during embryogenesis but perhaps also during adult vascular remodeling and angiogenesis.