Wnt1 is a proangiogenic molecule, enhances human endothelial progenitor function, and increases blood flow to ischemic limbs in a HGF‐dependent manner

Abstract

Human endothelial progenitor cells (hEPCs) participate in neovascularization of ischemic tissues. Function and number of hEPCs decline in patients with cardiovascular disease, and therapeutic strategies to enhance hEPC function remain an important field of investigation. The Wnt signaling system, comprising 19 lipophilic proteins, regulates vascular patterning in the developing embryo. However, the effects of Wnts on hEPCs and the adult vasculature remain unclear. We demonstrate here that Wnt1 is expressed in a subset of endothelial cells lining the murine embryonic dorsal aorta and is reactivated in malignant angiosarcoma, suggesting a strong association of Wnt1 with angiogenesis. We investigate the effects of Wnt1 in enhancing hEPC function and blood flow to ischemic tissues and show that Wnt1 enhances the proliferative and angiogenic functions of hEPCs in a hepatocyte growth factor (HGF)-dependent manner. Injection of Wnt1-expressing hEPCs increases blood flow and capillary density in murine ischemic hindlimbs. Furthermore, injection of Wnt1 protein alone similarly increases blood flow and capillary density in ischemic hindlimbs, and this effect is associated with increased HGF expression in ischemic muscle. These findings demonstrate that Wnt1, a marker of neural crest cells and hitherto unknown angiogenic function, is a novel angiogenic protein that is expressed in developing endothelial cells, exerts salutary effects on postnatal hEPCs, and can be therapeutically deployed to increase blood flow and angiogenesis in ischemic tissues.

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

“…Several factors might contribute to this clinically relevant anti-angiogenic role of WIF1 such as: (1) a decrease in VEGF transcription caused by a decrease in nuclear b-catenin, a known promoter of angiogenesis by an increase in VEGF expression (Skurk et al, 2005); (2) a decrease in VEGF half-life because of a decrease in CD44, a well-established proteolysis inhibitor of VEGF (Jones et al, 2000); (3) an increase in p53 expression, as the loss of p53 has been correlated with an increased VEGF expression and tumor angiogenesis (Linderholm et al, 2001); (4) a decrease in WNT1, a protein shown to stimulate the proliferation and angiogenic functions of human endothelial cells (Wright et al, 1999;Gherghe et al, 2011); and (5) a decrease in the endothelial cell-cell adhesion molecule CD31, a protein required for neovascularization (DeLisser et al, 1997). In early-stage cervical cancer, CD31 expression is significantly associated with lymphatic vascular space invasion and tumor size (Silva-Filho et al, 2006).…”

Molecular and Cellular Aspects of Calcific Aortic Valve Disease

“…Likewise, active Wnt/LRP receptor/beta-catenin signaling is necessary for the function of EC progenitors 62, 85 and -- with BMP / ALK receptor/ Smad pathways – it promotes the endothelial-mesenchymal transition (EnMT) necessary to create cardiac valves 86 and epicardial fibroblasts 87 . These same morphogenetic pathways appear to participate in the pathobiology of cardiovascular calcification and post-natal valve homeostasis.…”

The Role of the VEGF-C/VEGFRs Axis in Tumor Progression and Therapy

“…A proto-oncogene protein Wnt1 can induce tumor growth and angiogenesis [53,54]. With regards to lymphangiogenesis, however, a recent study showed that Wnt1 could protect against melanoma progression by suppressing melanoma-derived VEGF-C expression, followed by reduced lymphangiogenesis and metastasis [55].…”