Expression of EphrinB2 Identifies a Stable Genetic Difference Between Arterial and Venous Vascular Smooth Muscle as Well as Endothelial Cells, and Marks Subsets of Microvessels at Sites of Adult Neovascularization

Abstract

The transmembrane ligand ephrinB2 and its receptor tyrosine kinase EphB4 are molecular markers of embryonic arterial and venous endothelial cells, respectively, and are essential for angiogenesis. Here we show that expression of ephrinB2 persists in adult arteries where it extends into some of the smallest diameter microvessels, challenging the classical view that capillaries have neither arterial nor venous identity. EphrinB2 also identifies arterial microvessels in several settings of adult neovascularization, including tumor angiogenesis, contravening the dogma that tumor vessels arise exclusively from postcapillary venules. Unexpectedly, expression of ephrinB2 also defines a stable genetic difference between arterial and venous vascular smooth muscle cells. These observations argue for revisions of classical concepts of capillary identity and the topography of neovascularization. They also imply that ephrinB2 may be functionally important in neovascularization and in arterial smooth muscle, as well as in embryonic angiogenesis.

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

“…The same analysis at P6 (Supplementary Figure S1C,D) showed patches of strong ephrinB2 activity interleaved with similarly sized regions of relatively little reporter activity. We surmise that the lacZ positive patches seen in sections and whole mounts of postnatal lung correspond to arterial domains of the alveolar microvasculature (Gale et al, Shin et al, 2001). Expression patterns of native ephrinB2 were confirmed in E14 and P6 lung by staining with an alkaline-phosphatase coupled EphB4 receptor probe, which specifically recognizes ephrinB2 (Supplementary Figure S1E,F).…”

“…We, therefore, analyzed lungs for ephrinB2 expression. Using ␤-galactosidase expression in ephrinB2 lacZ knockin mice (Shin et al, 2001) as a reporter for ephrinB2 expression in the lung, we found that ephrinB2 changed its principal site of expression between embryonic and postnatal stages. Although ephrinB2 was readily detected on larger arteries at embryonic day (E) 17 (data not shown), anti-␤-galactosidase immunoreactivity did not detectably overlap with the PECAM-1 positive microvasculature surrounding ingrowing branches ( Fig.…”

Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer

“…In murine models, ephrin-B2 is expressed in the arterial ECs but not in the venous ECs (Wang et al, 1998;Adams et al, 1999). Ephrin-B2 is also expressed in the vascular smooth muscle cells of arteries (Shin et al, 2001). Wang et al (1998) reported that ephrin-B2s on arterial ECs interact with EphB4s on venous ECs, and Zhang et al (2001) showed that stromal cells expressing ephrin-B2 are involved in vascular network formation and proliferation of ECs.…”

“…Disruption of specific Eph receptors and ligands (including ephrin-B2) leads to defective vessel remodelling, organisation, and sprouting resulting in embryonic death (Wang et al, 1998;Adams et al, 1999;Gale and Yancopoulos, 1999;Helbling et al, 2000). Coordinated expression of the Eph/ephrin system determines the phenotype of embryonic vascular structures: ephrin-B2 is present on arterial endothelial cells (ECs), whereas EphB4 is present on venous ECs (Gale and Yancopoulos, 1999;Shin et al, 2001). Recently, specific Ephs and ephrins have been implicated in tumour growth and angiogenesis.…”

Optimality in the developing vascular system: Branching remodeling by means of intussusception as an efficient adaptation mechanism

“…Recruitment of periendothelial cells and their prolonged association with the larger pillars, probably stabilise these structures. Angiopoietins (Ang) and their Tie receptors (Folkman and D'Amore, 1996), PDGF-B (Hellstrom et al, 1999) and monocyte chemotactic protein 1 (Shyy et al, 1994), ephrins and Eph-B receptors (Gale et al, 2001;Shin et al, 2001) are likely candidates for the mediation of such cell-cell interactions. The vasculature of knockout mice lacking Ang-1 and Tie-2 remains at a primitive stage of development and fails to undergo further remodeling in knockout mice homozygous for Ang-1 (Suri et al, 1996).…”