Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice.

Abstract

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.

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

“…Vascular endothelial injury is an important risk factor for atherosclerosis and restenosis. To study the repair and remodeling processes, in previous studies, endothelial injury has been induced mechanically by (i) different diameters of angioplasty guide wire, [20][21][22][23] (ii) spring wire, 22 (iii) ligating the arteries using 9-0 nylon sutures, 23 (iv) placing a cuff, 24 (v) balloon distension, (vi) air desiccation and (vii) treatment with chemicals that selectively remove endothelial cells. However, shortcomings in most of these methods are unavoidable.…”

Nontranscriptional actions of the glucocorticoid receptor

“…Enhanced NO production by administration of the eNOS substrate Larginine or upregulation of eNOS by statins confers stroke protection [73,74,75], and transgenic mice overexpressing eNOS show decreased leukocyte accumulation and reduced vascular lesion formation following vascular injury [76]. Conversely, mice with targeted disruption of eNOS (eNOS −/− ) exhibit increased vascular inflammation and larger cerebral infarctions following experimental ischemia [77,78], while inhibition of NOS activity decreases cerebral blood flow and increases infarct size after ischemia [79].…”

NO: an inhibitor of cell death

“…Moreover, NO from either NO donors or transfected iNOS protected endothelial cells from apoptosis induced by a variety of treatments (see Table 1), including LPS, 30,31 LPS plus arsenite, 32 angiotensin II, 33 caspase-3 overexpression 34 and TNFa. 35 Thus, endogenous NO or related molecules probably play a protective role in endothelial cells, in keeping with their anti-atherogenic and generally salutary functions 36 (see the article by Dimmeler and Zeiher in this issue).…”