Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesis

Abstract

We recently isolated a novel angiogenesis inhibitor, vasohibin-1, and its homologue, vasohibin-2. In this study we characterize the role of these 2 molecules in the regulation of angiogenesis. In a mouse model of subcutaneous angiogenesis, the expression of endogenous vasohibin-1 was low in proliferating ECs at the sprouting front but high in nonproliferating endothelial cells (ECs) in the termination zone. In contrast, endogenous vasohibin-2 was preferentially expressed in mononuclear cells mobilized from bone marrow that infiltrated the sprouting front. When applied exogenously, vasohibin-1 inhibited angiogenesis at the sprouting front where endogenous vasohibin-1 was scarce but did not influence vascularity in the termination zone where endogenous vasohibin-1 was enriched. Exogenous vasohibin-2 prevented the termination of angiogenesis in the termination zone and increased vascularity in this region. Angiogenesis was persistent in the termination zone in the vasohibin-1 knockout mice, whereas angiogenesis was deficient at the sprouting front in the vasohibin-2 knockout mice. Supplementation of deficient proteins normalized the abnormal patterns of angiogenesis in the vasohibin knockout mice. These results indicate that vasohibin-1 is expressed in ECs in the termination zone to halt angiogenesis, whereas vasohibin-2 is expressed in infiltrating mononuclear cells in the sprouting front to promote angiogenesis. (Blood. 2009; 113:4810-4818)

Vasohibin-2 Expressed in Human Serous Ovarian Adenocarcinoma Accelerates Tumor Growth by Promoting Angiogenesis

“…Because of the similarity between VASH1 and VASH2, we examined their expression and function by the use of hypoxia-induced subcutaneous angiogenesis in mice. Our analysis revealed that VASH1 is mainly expressed in endothelial cells in the termination zone to halt angiogenesis, whereas VASH2 is mainly expressed in mononuclear cells mobilized from the bone marrow in the sprouting front to stimulate angiogenesis (16). Thus, these 2 VASH family members regulate angiogenesis perhaps in a seemingly contradictory manner.…”

“…We previously reported that VASH1 inhibits angiogenesis whereas VASH2 promotes it (16). We therefore examined the vasculature in the tumors and found a significant decrease in angiogenesis in tumors derived from either SKOV-3 or DISS sh-VASH2 cells (Fig.…”

“…VASH2 À/À mice on a C57BL/6 background were previously described (16). All of the animal experiments were approved by Tohoku University Center for Gene Research and carried out under the guidelines for animal experimentation of Tohoku University.…”

“…VASH2 can be expressed in bone marrow-derived CD11b þ mononuclear cells (16). To avoid the possible involvement of recipient VASH2, we planned to use VASH2 (À/À) mice.…”

Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via JUN proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2

“…VASH1 is located in the cytoplasm of endothelial cells and was first identified as a negative regulator of angiogenesis [2,3]. VASH2 is a homolog of VASH1, and was shown to stimulate angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis [3].…”