Moderate consumption of alcohol (ethanol) is a negative risk factor for atherosclerosis and its clinical sequelae myocardial infarction, ischemic stroke and peripheral vascular disease. Little is known about the precise cell signaling and molecular mechanisms whereby ethanol may elicit its putative cardioprotective effects. We have previously reported that while EtOH stimulates the growth and migration of endothelial cels (EC), it inhibits vascular smooth muscle cell (SMC) growth and migration. Given the key role of both EC and SMC in the pathophysiology of atherosclerosis, the opposing effects of EtOH on these vascular cells might be expected to be synergistically cardioprotective and thus are of considerable clinical interest. Moreover, our preliminary data show that daily moderate alcohol feeding markedly inhibits intima-media thickening following carotid ligation injury in the mouse. EC and SMC express Notch receptors and several groups, including ours, have described a critical role for Notch signaling in the regulation of adult EC and SMC differentiation, proliferation and apoptosis. The expression of several components of the Notch pathway, including receptors and downstream target genes hes and hrt, are altered after experimentally induced vascular injury. Our data also demonstrate a differential effect of EtOH on Notch signaling in EC and SMC, - stimulatory and inhibitory, respectively, and further, implicate this pathway in mediating both EtOH's promotion of EC proliferation and it's attenuation of SMC proliferation. The transmembrane protein Nogo-B, expressed by both EC and SMC and in intact vessels, has recently been identified as a regulator of vascular remodeling, limiting the progression of vascular lesions after injury. Of interest, Nogo-B reportedly has opposing effects on vascular cells, promoting the migration of EC, but inhibiting the migration of SMC, possibly reflecting differences in receptor expression between the two cell types. Our preliminary data show that EtOH modulates Nogo-B expression in vascular cells. Despite a role for both Notch and Nogo in vascular remodeling regulation, and a differential effect of each in EC and SMC with respect to phenotype regulation, no studies to date have investigated an interaction of Nogo and Notch, much less as targets for alcohol. Our central hypothesis is that ethanol stimulates EC, and inhibits SMC growth and thus inhibits vascular remodeling in a Notch-dependent manner, mediated via Nogo-B. We will test this hypothesis using cultured human coronary artery EC and SMC in vitro in conjunction with in vivo studies utilizing the carotid ligation 'flow-restriction'model of vascular injury and remodeling in the mouse. Since changes in EC and SMC growth plays a prominent role in the pathogenesis of vascular disease, modulation of these processes by ethanol in a Nogo-B-dependent fashion represents a novel and potentially important mechanism underlying ethanol's cardioprotective effect. Because the mortality from cardiovascular disease is so high, deciphering a mechanism whereby a substance can protect against it is clearly of major clinical importance and significance. !

Public Health Relevance

Moderate alcohol consumption protects against cardiovascular disease. These experiments will provide exciting new mechanistic information central to our understanding of how alcohol mediates its differential effects on endothelial and smooth muscle cell growth, processes that are integral to the development of cardiovascular disease. Deciphering the cellular and molecular mechanisms mediating alcohol's cardiovascular protective effects should enable the design of novel therapies for cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA020365-01A1
Application #
8242915
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Orosz, Andras
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$180,444
Indirect Cost
$62,891
Name
University of Rochester
Department
Surgery
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kennedy, Eimear; Mooney, Ciaran J; Hakimjavadi, Roya et al. (2014) Adult vascular smooth muscle cells in culture express neural stem cell markers typical of resident multipotent vascular stem cells. Cell Tissue Res 358:203-16
Redmond, Eileen M; Liu, Weimin; Hamm, Katie et al. (2014) Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling. PLoS One 9:e84122
Morrow, David; Hatch, Ekaterina; Hamm, Katie et al. (2014) Flk-1/KDR mediates ethanol-stimulated endothelial cell Notch signaling and angiogenic activity. J Vasc Res 51:315-24
Redmond, Eileen M; Hamm, Katie; Cullen, John P et al. (2013) Inhibition of patched-1 prevents injury-induced neointimal hyperplasia. Arterioscler Thromb Vasc Biol 33:1960-4