The interplay of cyclic stretch and vascular endothelial growth factor in regulating the initial steps for angiogenesis.
Angiogenesis is regulated by chemical and mechanical factors in vivo. The regulatory role of mechanical factors and how chemical and mechanical angiogenic regulators work in concert remains to be explored. We investigated the effect of cyclic uniaxial stretch (20%, 1 Hz), with and without the stimulation of vascular endothelial growth factor (VEGF), on sprouting angiogenesis by employing a stretchable three-dimensional cell culture model. When compared to static controls, stretch alone significantly increased the density of endothelial sprouts, and these sprouts aligned perpendicular to the direction of stretch. The Rho-associated kinase (ROCK) inhibitor Y27632 suppressed stretch-induced sprouting angiogenesis and associated sprout alignment. While VEGF is a potent angiogenic stimulus through ROCK-dependent pathways, the combination of VEGF and stretch did not have an additive effect on angiogenesis. In the presence of VEGF stimulation, the ROCK inhibitor suppressed stretch-induced sprout alignment but did not affect stretch-induced sprout density; in contrast, the receptor tyrosine kinase (RTK) inhibitor sunitinib had no effect on stretch-induced alignment but trended toward suppressed stretch-induced sprout density. Our results suggest that the formation of sprouts and their directionality do not have completely identical regulatory pathways, and thus it is possible to separately manipulate the number and pattern of new sprouts.
Dept. of Medicine, Div. of Nephrology, University of Utah School of Medicine, Salt Lake City, UT, 84112; Dept. of Bioengineering, University of Utah, Salt Lake City, UT, 84112.
Justin R
JR
Wilkins
Daniel B
DB
Pike
Christopher C
CC
Gibson
Li
L
Li
Yan-Ting
YT
Shiu
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D001696:Biomechanical Phenomena / Q000502:physiology*; D002417:Cattle; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D013314:Stress, Mechanical; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000577:Amides; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C108830:Y 27632; D054460:rho-Associated Kinases
Rho-associated kinase; cyclic uniaxial stretch; mechanotransduction; receptor tyrosine kinase; vascular endothelial growth factor