Long-Term and Sustained COMP-Ang1 Induces Long-Lasting Vascular Enlargement and Enhanced Blood Flow

Abstract

Abstract-Vascular enlargement is a characteristic feature of angiopoietin-1 (Ang1)-induced changes in adult blood vessels. However, it is unknown whether tissues having Ang1-mediated vascular enlargement have more blood flow or whether the enlargement is reversible. We have recently created a soluble, stable and potent Ang1 variant, COMP-Ang1.In the present study, we investigated the effects of varied dose and duration of COMP-Ang1 on vascular enlargement and blood flow in the tracheal microvasculature of adult mice and explored a possible mechanism of long-lasting vascular enlargement. We found that COMP-Ang1 administered by adenoviral vector induced long-lasting vascular enlargement and increased tracheal blood flow. In contrast, short-term administration of COMP-Ang1 recombinant protein induced transient vascular enlargement that spontaneously reversed within a month. In both cases, the vascular enlargement resulted from endothelial proliferation. The COMP-Ang1-induced vascular remodeling is mediated mainly through Tie2 activation. Sustained overexpression of Tie2 could participate in the maintenance of vascular changes. Together, our findings indicate that sustained treatment with COMP-Ang1 can produce long-lasting vascular enlargement and increased blood flow. Key Words: angiopoietin-1 Ⅲ COMP-Ang1 Ⅲ vascular enlargement Ⅲ blood flow A ngiopoietin-1 (Ang1) is known to be a ligand to Tie2 tyrosine kinase receptor expressed on endothelial cells. 1 Ang1/Tie2 signaling is thought be involved in branching and remodeling of the primitive vascular network and in the recruitment of mural cells during development. 2,3 Transgenic overexpression of Ang1 using the skin-specific keratin-14 promoter produces leakage-resistant and enlarged vessels with an increased number of endothelial cells in skin. 4,5 Gene transfer of Ang1 into ischemic tissues produces notably enlarged blood vessels. 6,7 Baffert et al recently identified that Ang1-induced vascular enlargement could be the result of endothelial proliferation in trachea mucosa. 8 Thus, a cardinal feature of Ang1-induced vascular remodeling is vascular enlargement resulting from endothelial cell proliferation in adult animals. 4 -8 Given that Ang1-induced therapeutic benefits correlated with vascular enlargement in the ischemic tissues, 6,7,9 enhanced blood flow through blood vessels enlarged by Ang1 treatment could provide a great therapeutic benefit to ischemic peripheral tissues. However, it is not known whether the tissues having Ang1-mediated enlarged vessels have more blood flow. In addition, the effective dose and treatment period of Ang1 for inducing effective vascular enlargement is not known. Moreover, it is not known whether Ang1-mediated vascular enlargement regresses when Ang1 stimulation is withdrawn.We have recently developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. 10 To create this protein, we replaced the amino-terminal portion of Ang1 with the short coiled-coil domain of cartilage oligomeric matrix protein (COMP). COMP-Ang1 is more po...

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.…”

Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis

“…Their cognate TIE-2 receptor (and a closely related orphan receptor, TIE-1) is mainly expressed in endothelial cells. They lack mitogenic activity toward endothelial cells [although conflicting data are emerging that showed otherwise (22,23)] but affect distinct aspects of vascular development (24,25). Transgenic mice lacking ANG-1 or overexpressing ANG-2 have defects attributed to disrupted interaction between endothelial and perivascular cells (15,25).…”

“…Indeed, persistent perivascular cell recruitment in vessels composed of TIE-2 -deficient endothelial cells that subsequently apoptosed strongly supports this contention (103,104). Furthermore, overexpression of ANG-1 in the skin and lung failed to show evidence of enhanced recruitment of perivascular cells to the vessels (23,27,105). Dilated and pericyte-scarce vessels in " or # indicates increased or decreased expression levels compared with control tumors; + indicates the factor was detectable but levels not quantified against control tumors; = indicates unchanged expression levels; -indicates no effect on the outcome.…”

Negative Regulation of VEGF-Induced Vascular Leakage by Blockade of Angiotensin II Type 1 Receptor

“…These difficulties are attributable to its unique structural characteristics. Although it has been reported that the COMP-Ang1, which is a potent Ang1 variant produced by replacing the N-terminal portion of Ang1 with the short coiled-coil domain of cartilage oligomeric matrix protein, induces angiogenesis, vascular enlargement, and lymphangiogenesis, 17 this factor is still under development for clinical use. Therefore, other candidate molecules that inhibit vascular permeability are sought for use in combination with VEGF in therapeutic angiogenesis.…”