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 affect ed by genetic makeup and environment, we have (a) generated a reproduc ible mouse model of neointimal growth; (b) evaluated the effect of dis ruption of a single gene, endothelial nitric oxide synthase, believed to be central to intimal growth, and (c) examined the modifying effect s of gender and pregnancy upon the vascular response, Cuff placement a round the femoral artery causes reproducible intimal growth. We assess ed the response to injury by quantitative morphometry, measuring the i ntimal 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 wil d-type females. Most dramatic, however, is the effect of pregnancy, wh ich essentially abolishes the intimal response to injury, even overrid ing the effect of eNOS mutation. We conclude that eNOS deficiency is a genetic predisposition to intimal proliferation that is enhanced by m ale gender, and that may be overridden by pregnancy.