Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status.
Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G₀/G₁ cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent.
Division of Vascular Surgery and the Institute for BioNanotechnology in Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Melissa E
ME
Hogg
Vinit N
VN
Varu
Ashley K
AK
Vavra
Daniel A
DA
Popowich
Monisha N
MN
Banerjee
Janet
J
Martinez
Qun
Q
Jiang
Joseph E
JE
Saavedra
Larry K
LK
Keefer
Melina R
MR
Kibbe
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001391:Azo Compounds / Q000378:metabolism / Q000494:pharmacology; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D002369:Castration; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000032:analysis / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006728:Hormones / Q000032:analysis / Q000096:biosynthesis; D006965:Hyperplasia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058426:Neointima / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D001391:Azo Compounds; D018797:Cell Cycle Proteins; D006728:Hormones; D020030:Nitric Oxide Donors; C452539:diazeniumdiolate; D009569:Nitric Oxide
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