title: Differential effects of cyclic stretch on bFGF- and VEGF-induced sprouting angiogenesis.
abstract: How mechanical factors affect angiogenesis and how they and chemical angiogenic factors work in concert remain not yet well-understood. This study investigated the interactive effects of cyclic uniaxial stretch and two potent proangiogenic molecules [basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)] on angiogenesis using a stretchable three-dimensional (3-D) cell culture model. Endothelial cells seeded atop a 3-D collagen gel underwent sprouting angiogenesis while being subjected to either 10 or 20% cyclic uniaxial stretch at a frequency of either 1/12 or 1 Hz, in conjunction with an elevated concentration of bFGF or VEGF. Without the presence of additional growth factors, 10 and 20% stretch at 1 Hz induced angiogenesis and the perpendicular alignment of new sprouts, and both inductive effects were abolished by cytochalasin D (an actin polymerization inhibitor). While "10% stretch at 1 Hz," "20% stretch at 1 Hz," bFGF, and VEGF were strong angiogenesis stimulants individually, only the combination of "20% stretch at 1 Hz" and bFGF had an additive effect on inducing new sprouts. Interestingly, the combination of "20% stretch at a lower frequency (1/12 Hz)" and bFGF decreased sprouting angiogenesis, even though the level of perpendicular alignment of new sprouts was the same for both stretch frequencies. Taken together, these results demonstrate that both stretch frequency and magnitude, along with interactions with various growth factors, are essential in mediating formation of endothelial sprouts and vascular patterning. Furthermore, work in this area is warranted to elucidate synergistic or competitive signaling mechanisms.
authors.affiliation: Div. of Nephrology, Dept. of Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84112; Dept. of Bioengineering, University of Utah, Salt Lake City, UT, 84112.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Wilkins
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Pike
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Gibson
authors.forename: Atsutoshi
authors.initials: A
authors.lastname: Kubota
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Shiu
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000008:administration & dosage*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000235:genetics*; D013314:Stress, Mechanical; D023822:Tissue Engineering; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D005346:Fibroblast Growth Factors
keywords: actin filaments; angiogenesis; basic fibroblast growth factor; cyclic stretch; vascular endothelial growth factor