@article {1626096,
	title = {Novel engineered, membrane-tethered VEGF-A variants promote formation of filopodia, proliferation, survival, and cord or tube formation by endothelial cells via persistent VEGFR2/ERK signaling and activation of CDC42/ROCK pathways},
	journal = {FASEB J},
	volume = {35},
	number = {12},
	year = {2021},
	month = {2021 12},
	pages = {e22036},
	abstract = {Therapeutic angiogenesis would be clinically valuable in situations such as peripheral vascular disease in diabetic patients and tissue reperfusion following ischemia or injury, but approaches using traditional isoforms of vascular endothelial growth factor-A (VEGF) have had little success. The isoform VEGF165 is both soluble and matrix-associated, but can cause pathologic vascular changes. Freely diffusible VEGF121 is not associated with pathologic angiogenesis, but its failure to remain in the vicinity of the targeted area presents therapeutic challenges. In this study, we evaluate the cellular effects of engineered VEGF variants that tether extracellular VEGF121 to the cell membrane with the goal of activating VEGF receptor 2 (VEGFR2) in a sustained, autologous fashion in endothelial cells. When expressed by primary human retinal endothelial cells (hRECs), the engineered, membrane-tethered variants eVEGF-38 and eVEGF-53 provide a lasting VEGF signal that induces cell proliferation and survival, increases endothelial permeability, promotes the formation of a cord/tube network, and stimulates the formation of elongated filopodia on the endothelial cells. The engineered VEGF variants activate VEGFR2, MAPK/ERK, and the Rho GTPase mediators CDC42 and ROCK, activities that are required for the formation of the elongated filopodia. The sustained, pro-angiogenic activities induced by eVEGF-38 and eVEGF-53\&nbsp;support the potential of engineered VEGF variants-overexpressing endothelial cells as a novel combination of gene and cell-based therapeutic strategy for stimulating endothelial cell-autologous therapeutic angiogenesis.},
	keywords = {cdc42 GTP-Binding Protein, Cell Movement, Cell Proliferation, Endothelial Cells, Gene Expression Regulation, Humans, MAP Kinase Signaling System, Mutation, Neovascularization, Physiologic, Pseudopodia, Retina, rho-Associated Kinases, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2},
	issn = {1530-6860},
	doi = {10.1096/fj.202100448RR},
	author = {Shen, Junhui and Rossato, Franco Aparecido and Cano, Issahy and Ng, Yin Shan Eric}
}
