Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.
To begin to dissect atherogenesis as a complex genetic disorder affected by genetic makeup and environment, we have (a) generated a reproducible mouse model of neointimal growth; (b) evaluated the effect of disruption of a single gene, endothelial nitric oxide synthase, believed to be central to intimal growth, and (c) examined the modifying effects of gender and pregnancy upon the vascular response. Cuff placement around the femoral artery causes reproducible intimal growth. We assessed the response to injury by quantitative morphometry, measuring the intimal to medial (I/M) volume ratio. In wild-type mice, cuff placement causes pronounced intimal proliferation without affecting the media, resulting in I/M ratios of 31% (SV129 males) and 27% (C57BL/6 males). eNOS mutant male mice have a much greater degree of intimal growth (I/M ratio of 70%). Female mice show less intimal response than do males, although eNOS mutant female mice still have more response than do wild-type females. Most dramatic, however, is the effect of pregnancy, which essentially abolishes the intimal response to injury, even overriding the effect of eNOS mutation. We conclude that eNOS deficiency is a genetic predisposition to intimal proliferation that is enhanced by male gender, and that may be overridden by pregnancy.
Moroi
M
M
Cardiovascular Research Center and Cardiac Unit, Massachusetts General Hospital-East, Charlestown, MA 02129, USA.
Zhang
L
L
Yasuda
T
T
Virmani
R
R
Gold
H K
HK
Fishman
M C
MC
Huang
P L
PL
D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000254:growth & development / Q000293:injuries / Q000378:metabolism*; D005260:Female; D005263:Femoral Artery / Q000254:growth & development / Q000293:injuries / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D012737:Sex Factors; D017539:Tunica Intima / Q000254:growth & development / Q000293:injuries / Q000378:metabolism
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase