Tetrahydrobiopterin determines vascular remodeling through enhanced endothelial cell survival and regeneration.

Abstract

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.

• Authors: Ziad A Ali, Ruth Rinze, Gillian Douglas, Yanhua Hu, Qingzhong Xiao, Wei Qi, Eileen McNeill, Christina Bursill, Isaac George, David R Greaves, Qingbo Xu, Keith M Channon
• Journal: Circulation (Circulation) Vol. 128 Issue 11 Suppl 1 Pg. S50-S58 (Sep 10 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 24030421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biopterin
• sapropterin

Topics

• Animals
• Biopterin (analogs & derivatives, physiology)
• Cell Survival (physiology)
• Endothelial Cells (pathology, physiology)
• Humans
• Hyperplasia (pathology, surgery)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Neointima (pathology, surgery)
• Regeneration (physiology)
• Transplants
• Up-Regulation (physiology)
• Vena Cava, Inferior (cytology, physiology)