Arterial-Venous Segregation by Selective Cell Sprouting: An Alternative Mode of Blood Vessel Formation

Abstract

Blood vessels form de novo (vasculogenesis) or upon sprouting of capillaries from pre-existing vessels (angiogenesis). Using high resolution imaging of zebrafish vascular development we discovered a third mode of blood vessel formation whereby the first embryonic artery and vein, two unconnected blood vessels, arise from a common precursor vessel. The first embryonic vein formed by selective sprouting of progenitor cells from the precursor vessel, followed by vessel segregation. These processes were regulated by the ligand EphrinB2 and its receptor EphB4, which are expressed in arterial-fated and venous-fated progenitors, respectively, and interact to orient the direction of progenitor migration. Thus, directional control of progenitor migration drives arterial/venous segregation and generation of separate parallel vessels from a single precursor vessel, a process essential for vascular development.

Vascular Development in the Zebrafish

“…One of these studies also reported that Shh and Vegf signaling act upstream of and control Sox7 (Pendeville et al 2008). Interestingly, another recent study has also suggested that there may be selective cell segregation required for proper A-V formation, with distinct steps of cell segregation into arterial and venous fates are controlled by different signaling pathways including VegfA, VegfC, Notch, and Ephrin B2 (Herbert et al 2009). …”

“…Netrin1 and its receptor, UNC5B, are required for the proper vessel formation, although conflicting data exist as to whether netrin signaling plays a repulsive role Larrivee et al 2007;Bouvree et al 2008), an attractive role (Navankasattusas et al 2008), or, potentially, both (Yang et al 2007) in the developing vasculature. In addition to their role in arterialvenous specification (Herbert et al 2009), ephrins are also implicated in vascular sprouting in zebrafish. Morpholino knockdown of ephrinB2 causes tip cells to decrease filopodial activity in intersegmental vessels consistent with the observation that ephrin signaling promotes angiogenic activity (Wang et al 1998).…”

Tips, Stalks, Tubes: Notch-Mediated Cell Fate Determination and Mechanisms of Tubulogenesis during Angiogenesis

“…This process involves Rho-dependent kinase and is not known to invoke vesicular trafficking. Another model, termed "selective sprouting," is supported by studies in the developing zebrafish cardinal vein (Herbert et al 2009). The selective sprouting model stipulates that venous endothelial cells migrate from the dorsal aorta to surround erythrocytes and are retained by VEGF-A/VEGFR-2 signaling, a process analogous to vasculogenesis during embryogenesis.…”

The Role of EphB4 and Ephrin-B2 Interactions in Prostate Cancer Models of Intravasation and Extravasation

“…The modelling of two major vessels, the dorsal aorta and the cardinal vein, during embryonic development requires repulsive signalling between ephrin-B2 and EphB4 in endothelial cells (ECs) [101,102]. Initially shown in zebrafish [103], and then in mouse [104], the dorsal aorta forms first and harbours a mixed population of venous (EphB4+) and arterial progenitors (ephrin-B2+). Both studies have shown that the formation of the cardinal vein is regulated by repulsive signalling between EphB4 and ephrin-B2.…”

“…Signalling between both EphB4 and ephrin-B2 repels venous ECs from arterial ECs generating an EphB4+ cardinal vein [103,104]. During the early stages of embryo development lymphatic ECs differentiate from the cardinal vein and other venous derivatives [105].…”