Total or endothelium specific PGC-1α deficiency is associated with alterations in vascular function in mice

Abstract

Endothelial dysfunction is a common alteration in several cardiovascular diseases that is produced by increased oxidative stress and a vascular pro-inflammatory state. This condition is associated with an imbalance in the relative contribution of endothelium-derived relaxing factors such as nitric oxide (NO) and contracting factors such as endothelin-1 (ET-1) that results in alterations in vascular function. PGC-1α is a transcriptional coactivator that regulates oxidative metabolism and participates in the control of oxidative stress. Previous in vitro studies suggest that PGC-1α activity could prevent endothelial dysfunction induced by hyperglicaemia. The aim of this work was to analyze in vivo if PGC-1α deficiency results in alterations in vascular function. For that purpose, knockout mice for PGC-1α (KO) and mice with a specific deletion of PGC-1α in the vascular endothelium (Tg-TIE2-Cre/PGC-1af/-) were used. Aorta segments were set in an organ bath to perform vascular reactivity experiments in presence/absence of lipopolysaccharide (LPS). Aorta segments from PGC-1α KO mice showed increased vasoconstriction in response to noradrenaline (NA), angiotensin II (Ang II) and ET-1 in basal conditions and decreased relaxation in response to Ach after pre-incubation with LPS. Similarly, aorta segments from TIE mice showed increased vascular contraction in response to ET-1 and Ang II and decreased relaxation in response to Ach when LPS was present. The increased vasoconstrictor response was mediated by COX-2 activation as it was blocked in the presence of the COX-2 inhibitor meloxicam. The decreased relaxation in response to Ach in LPS-preincubated segments appears to be mediated by increased oxidative stress since it was attenuated in the presence of ROS scavengers. In conclusion, total or endothelium specific PGC-1α deficiency results in alterations in the vascular response of arterial segments to both vasoconstrictors and vasodilators, especially under an inflammatory challenge. Thus, PGC-1α might be a promising target of study against vascular diseases.