YC-1-mediated vascular protection through inhibition of smooth muscle cell proliferation and platelet function.
YC-1, a synthetic benzyl indazole derivative, is capable of stimulating endogenous vessel wall cyclic guanosine monophosphate (cGMP) production and attenuating the remodeling response to experimental arterial angioplasty. In an effort to investigate the mechanisms of this YC-1-mediated vasoprotection, we examined the influence of soluble YC-1 or YC-1 incorporated in a polyethylene glycol (PEG) hydrogel on cultured rat vascular smooth muscle cell (SMC) cGMP synthesis, SMC proliferation, and platelet function. Results demonstrate that soluble YC-1 stimulated SMC cGMP production in a dose-dependent fashion, while both soluble and hydrogel-released YC-1 inhibited vascular SMC proliferation in a dose-dependent fashion without effects on cell viability. Platelet aggregation and adherence to collagen were both significantly inhibited in a dose-dependent fashion by soluble and hydrogel-released YC-1. Arterial neointima formation following experimental balloon injury was significantly attenuated by perivascular hydrogel-released YC-1. These results suggest that YC-1 is a potent, physiologically active agent with major anti-proliferative and anti-platelet properties that may provide protection against vascular injury through cGMP-dependent mechanisms.
Tulis
David A
DA
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. dtulis@bcm.tmc.edu
Bohl Masters
Kristyn S
KS
Lipke
Elizabeth A
EA
Schiesser
Rachel L
RL
Evans
Alida J
AJ
Peyton
Kelly J
KJ
Durante
William
W
West
Jennifer L
JL
Schafer
Andrew I
AI
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D016893:Carotid Stenosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020100:Hydrogels / Q000008:administration & dosage; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley
D020100:Hydrogels; D007191:Indazoles; D010975:Platelet Aggregation Inhibitors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D011092:Polyethylene Glycols; D006152:Cyclic GMP