Submitted on July 2, 2008
Revised on May 11, 2009
Accepted on May 19, 2009
Vascular Endothelial Dysfunction with Aging: Endothelin-1 and Endothelial Nitric Oxide Synthase
Anthony John Donato1*, Lindsey B Gano1, Iratxe Eskurza, Annemarie E Silver1, Phillip E Gates2, Kristen L. Jablonski1, and Douglas R. Seals3
1 University of Colorado at Boulder
2 Peninsula Medical School, University of Exeter
3 University of Colorado-Boulder
* To whom correspondence should be addressed. E-mail: tony.donato{at}colorado.edu.
It is unknown if reductions in endothelium-dependent dilation (EDD) in older adults is associated with changes in the expression of major vasoconstrictor or vasodilator proteins in the vascular endothelium. Protocol 1: Endothelial cells (EC) were obtained from peripheral veins of 50 men: 27 young (22 ± 1 years) and 23 older (62 ± 1 years). EDD (brachial artery flow-mediated dilation) was lower (3.50 ± 0.44 vs. 7.68 ± 0.43%, P<0.001) and EC endothelin-1 (ET-1) (quantitative immunofluorescence) was greater (0.47 ± 0.06 vs. 0.32 ± 0.03, P < 0.05) in the older men. Endothelial nitric oxide synthase (eNOS) was not different in the two groups (P>0.05), whereas ser1177 phosphorylated eNOS (PeNOS), an activated form of eNOS, was greater in the older men (0.82 ± 0.15 vs. 0.40 ± 0.06, P < 0.05). EDD was inversely related to EC ET-1 (r = -0.37, P < 0.05). Protocol 2: Brachial artery EC ET-1 (0.99 ± 0.10 vs. 0.57 ± 0.10, P=0.01) and PeNOS (0.77 ± 0.09 vs. 0.44 ± 0.07, P < 0.05) were greater, and EDD (peak forearm blood flow to intra-brachial acetylcholine) was lower (P<0.05) in older (10.2 ± 0.9, n = 18) vs. young (14.7 ± 1.7, n = 15) healthy men. EDD was inversely related to expression of ET-1 (r=-0.39, P < 0.05). Protocol 3: ET-1 receptor A inhibition with BQ-123 restored 60% of the age-related impairment in carotid artery dilation to acetylcholine in B6D2F1 mice (5-7 mo, n = 8; 30 mo, n = 11; P < 0.05). Conclusions: ET-1 expression is increased in ECs of older men and related to reduced EDD, whereas ET-1 receptor A signaling tonically suppresses EDD in old mice. PeNOS is increased in older men, but not eNOS. Changes in ET-1 expression and bioactivity, but not eNOS, contribute to endothelial dysfunction with aging.
