Angiopoietin 1 causes vessel enlargement, without angiogenic sprouting,during a critical developmental period

Abstract

Early in development, endothelial cells proliferate, coalesce, and sprout to form a primitive plexus of undifferentiated microvessels. Subsequently,this plexus remodels into a hierarchical network of different-sized vessels. Although the processes of proliferation and sprouting are well studied and are dependent on the angiogenic growth factor VEGF, the factors involved in subsequent vessel remodeling are poorly understood. Here, we show that angiopoietin 1 can induce circumferential vessel enlargement, specifically on the venous side of the circulation. This action is due to the ability of angiopoietin 1 to promote endothelial cell proliferation in the absence of angiogenic sprouting; vessel growth without sprouting has not been ascribed to other vascular growth factors, nor has specificity for a particular segment of the vasculature. Moreover, angiopoietin 1 potently mediates widespread vessel enlargement only during a brief postnatal period, in particular, prior to the fourth postnatal week, corresponding to stages in which VEGF inhibition causes widespread vessel regression. These findings show that angiopoietin 1 has a potentially unique role among the vascular growth factors by acting to enlarge blood vessels without inducing sprouting, and also define a critical window of vascular plasticity in neonatal development. Finding the key molecular factors that regulate this plasticity may prove crucial to the further development of pro- and anti-angiogenic therapies.

Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis

“…In ES cell tumors, VE-PTP KO blood vessels were enlarged, extending the findings in yolk sacs of VE-PTP-deficient embryos (9,10), and strongly supporting the findings in explant models (31). Such a phenotype also resembles the effect of tissue-specific transgenic overexpression of the Tie2 ligand, Ang1 (21,32) or prolonged treatment with exogenous Ang1 (20,22). Importantly, the enlarged vessels in ES tumors could be returned to normal size by treatment with angiopoietin inhibitors.…”

“…The vessel enlargement seen in VE-PTP-null vessels resembled previous findings that activation of the angiopoietin-Tie2 pathway also results in an increase in vessel diameter (20)(21)(22)(23), although the effects of this pathway on vessel size have not yet been explored in tumor angiogenesis. To explore the role of the angiopoietin-Tie2 pathway, and possible regulation by VE-PTP, during tumor angiogenesis, we first asked whether manipulating the angiopoietin-Tie2 pathway could regulate blood vessel diameter in ES tumors.…”

“…To explore the role of the angiopoietin-Tie2 pathway, and possible regulation by VE-PTP, during tumor angiogenesis, we first asked whether manipulating the angiopoietin-Tie2 pathway could regulate blood vessel diameter in ES tumors. Therefore, teratomabearing mice were treated systemically with recombinant angiopoietin-1 protein (24), a reagent shown to activate Tie2 receptor tyrosine kinase in vivo through ligand-receptor interaction and to increase blood vessel diameter in certain settings (22).…”

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

“…26 Our results in vivo support FTY720-induced increases in cell migration and proliferation, as evidenced by increased length density, diameter, and branching on venules, a metric indicative of sprouting angiogenesis. 3,27 In contrast, other studies have reported that FTY720 actually inhibits vascular endothelial growth factor-induced vascular permeability and angiogenesis. [28][29][30] The antiangiogenic effects of FTY720, though surprising based on its potent agonist activity, are proposed to occur as a result of functional antagonism.…”

VE-PTP controls blood vessel development by balancing Tie-2 activity

“…However, studies on the ability of Ang1 to stimulate proliferation of cultured endothelial cells are controversial, ranging from no effect Witzenbichler et al, 1998;Fujikawa et al, 1999) to mild effects (Koblizek et al, 1998;Teichert-Kuliszewska et al, 2001) to substantial effects (Kanda et al, 2005). The in vivo studies with Ang1 and COMP-Ang1 in newborns (Cho et al, 2005;Thurston et al, 2005;Kim et al, 2007) suggest that vessel enlargement was accompanied by endothelial cell proliferation, establishing that Tie-2 can stimulate proliferation of endothelial cells in vivo.…”