Perivascular delivery of blebbistatin reduces neointimal hyperplasia after carotid injury in the mouse.
Proliferation and migration of smooth muscle cells (SMC) require myosin II activity; thus, we examined whether blebbistatin, a cell-permeable selective inhibitor of myosin II ATP activity, would impair neointimal hyperplasia after vascular injury. Delivery of blebbistatin via a perivascular polymer cuff reduced neointimal formation by 73% and luminal obstruction by 75% after carotid denudation injury in C57BL/6 mice. Blebbistatin treatment was also associated with a reduction in cell density within the neointima; total number of cells (76 ± 7 to 27 ± 3 cells/high-powered field) and actin-positive cells (64 ± 4 to 24 ± 2 cells/high-powered field) in the neointima were reduced in blebbistatin-treated mice compared with vehicle-treated mice. In a model of vascular injury with an intact endothelium, implantation of a blebbistatin-secreting cuff after carotid ligation in FVB/N mice was associated with a 61% decrease in neointimal area and a significant decrease in luminal obstruction (88 ± 4% in vehicle-treated mice versus 36 ± 4% in blebbistatin-treated mice; p < 0.0001). In cultured rat aortic SMC, blebbistatin disrupted cellular morphology and actin cytoskeleton structure, and these effects were rapid and completely reversible. Blebbistatin had a dose-dependent inhibitory effect on DNA replication and cell proliferative responses to platelet-derived growth factor-BB, angiotensin II, and α-thrombin, migratory responses to serum, and migratory responses after blunt injury. In summary, perivascular delivery of blebbistatin reduced neointimal hyperplasia after carotid injury in the mouse.
McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
Jianhua
J
Huang
Jianxin
J
Zhang
Alokkumar
A
Pathak
Juxiang
J
Li
George A
GA
Stouffer
D000818:Animals; D020212:Carotid Artery Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage*; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D006576:Heterocyclic Compounds, 4 or More Rings; C472645:blebbistatin