Tetrahydrobiopterin Determines Vascular Remodeling Through Enhanced Endothelial Cell Survival and Regeneration

被引：18

作者：

Ali, Ziad A. ^{[1
,2
,3
,4
,5
]}

Rinze, Ruth ^{[4
,5
]}

Douglas, Gillian ^{[4
,5
]}

Hu, Yanhua ^{[6
]}

Xiao, Qingzhong ^{[6
]}

Qi, Wei ^{[1
,2
]}

McNeill, Eileen ^{[4
,5
]}

Bursill, Christina ^{[4
,5
]}

George, Isaac ^{[1
,2
]}

Greaves, David R. ^{[7
]}

Xu, Qingbo ^{[6
]}

Channon, Keith M. ^{[4
,5
]}

机构：

[1] New York Presbyterian Hosp, Div Cardiol, Ctr Intervent Vasc Therapy, New York, NY 10032 USA

[2] Columbia Univ, New York, NY USA

[3] Cardiovasc Res Fdn, New York, NY USA

[4] John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England

[5] Univ Oxford, Oxford, England

[6] Kings Coll Hosp London, Div Cardiovasc, London, England

[7] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England

来源：

CIRCULATION | 2013年 / 128卷 / 11期

基金：

英国惠康基金;

关键词：

endothelial cells; endothelial progenitor cells; free radicals; nitric oxide synthase; remodeling; NITRIC-OXIDE SYNTHASE; CYCLOHYDROLASE-I OVEREXPRESSION; CIRCULATING PROGENITOR CELLS; APOE-DEFICIENT MICE; NEOINTIMAL FORMATION; GENE-EXPRESSION; REENDOTHELIALIZATION; ATHEROSCLEROSIS; ACTIVATION; STRESS;

D O I：

10.1161/CIRCULATIONAHA.112.000249

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-Endothelial cell (EC) survival and regeneration are important determinants of the response to vascular injury that leads to neointimal hyperplasia and accelerated atherosclerosis. Nitric oxide (NO) is a key regulator of EC and endothelial progenitor cell function, but the pathophysiological mechanisms that regulate endothelial NO synthase in endothelial regeneration remain unclear. Methods and Results-Endothelium-targeted overexpression of GTP cyclohydrolase (GCH) I increased levels of the endothelial NO synthase cofactor, tetrahydrobiopterin, in an EC-specific manner and reduced neointimal hyperplasia in experimental vein grafts in GCH/apolipoprotein E-knockout mice. These effects were mediated through enhanced donor-derived survival and recipient-derived repopulation of GCH transgenic ECs, revealed by tracking studies in Tie2-LacZ/GCH-Tg/apolipoprotein E-knockout recipient mice or donor grafts, respectively. Endothelial GCH overexpression increased endothelial NO synthase coupling and enhanced the proliferative capacity of ECs and circulating endothelial progenitor cell numbers after vascular injury. Conclusions-These observations indicate that endothelial tetrahydrobiopterin availability modulates neointimal hyperplasia after vascular injury via accelerated EC repopulation and growth. Targeting tetrahydrobiopterin-dependent endothelial NO synthase regulation in the endothelium is a rational therapeutic target to enhance endothelial regeneration and reduce neointimal hyperplasia in vascular injury states.

引用

页码：S50 / S58

页数：9

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