title: sFRP4 signalling of apoptosis and angiostasis uses nitric oxide-cGMP-permeability axis of endothelium.
abstract: Nitric oxide (NO) plays a critical role in endothelial functions such as cellular migration, vascular permeability and angiogenesis. Angiogenesis, the formation of new blood vessels from "pre-existing" ones is a carefully regulated process and essential during reproduction, development and wound healing. Previously our lab group reported that Secreted Frizzled-Related Protein 4 (sFRP4) could inhibit angiogenesis in both in vitro and in vivo conditions. sFRP4 belongs to a family of secreted glycoproteins that function as antagonists of the canonical Wnt signalling pathway. Although the pro-apoptotic role of sFRP4 is well discussed in literature, little is known in regards to its anti-angiogenic property. The objective of this study was to elucidate sFRP4 implications in NO biology of the endothelium. Results demonstrate that sFRP4 causes endothelial dysfunction by suppressing NO-cGMP signaling and elevating corresponding ROS levels. The imbalance between NO and ROS levels results in apoptosis and subsequent leakiness of endothelium as confirmed in vivo (Texas red/Annxin - CAM assay) and in vitro (Monolayer permeability assay) conditions. Furthermore utilizing peptides synthesized from the CRD domain of sFRP4, our results showed that while these peptides were able to cause endothelial dysfunctions, they did not cause apoptosis of the endothelial cells. Thereby confirming that sFRP4 can mediate its anti-angiogenic effect independent of its pro-apoptotic property. In conclusion, the current study reports that sFRP4-mediated anti-angiogenesis occurs as a result of impaired NO-cGMP signaling which in turn allow for elevation of redox levels and promotion of apoptosis of endothelial cells.
authors.affiliation: Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai 600044, India.
authors.forename: Uttara
authors.initials: U
authors.lastname: Saran
authors.affiliation: Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai 600044, India.
authors.forename: Krishna Priya
authors.initials: KP
authors.lastname: Mani
authors.affiliation: Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai 600044, India.
authors.forename: Uma Maheswari
authors.initials: UM
authors.lastname: Balaguru
authors.affiliation: Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai 600044, India.
authors.forename: Akila
authors.initials: A
authors.lastname: Swaminathan
authors.affiliation: Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai 600044, India.
authors.forename: Shunmugam
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
authors.forename: Arun M
authors.initials: AM
authors.lastname: Dharmarajan
authors.affiliation: Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai 600044, India; Department of Biotechnology, Anna University, Chennai 600044, India. Electronic address: soovro@yahoo.ca.
authors.forename: Suvro
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D006152:Cyclic GMP; D009569:Nitric Oxide; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins
keywords: Apoptosis; Endothelium; Nitric oxide; Reactive oxygen species; cGMP; sFRP4