PGC‐1α Activation Confers Plasticity in the Mediator of Dilation in Healthy and Diseased Human Arterioles

Abstract

BackgroundCoronary artery disease (CAD) and increased intraluminal pressure (IILP) shift the mediator of flow‐induced dilation (FID) from nitric oxide (NO) to hydrogen peroxide (H2O2) in the human microcirculation. PGC‐1α, a master regulator of mitochondrial biogenesis, regulates reactive oxygen species (ROS) production and blood pressure. PGC‐1α is decreased in vessels from CAD patients. It is not known whether this important regulator of cell function is critically involved in endothelial‐mediated changes in vascular tone.ObjectiveTo determine whether a stimulated increase in PGC‐1α levels can restore NO as the mediator of dilation in healthy vessels exposed to IILP, and in CAD vessels.MethodsHuman adipose arterioles were incubated overnight with ZLN005, a novel transcriptional activator of PGC‐1α, and subsequently cannulated on glass micropipettes. Healthy (non‐CAD) vessels were exposed to physiological pressure conditions (60mmHg) or IILP (150mmHg for 30 min). Diseased (CAD) vessels were only exposed to 60mmHg pressure. Dilation was elicited by flow in the absence and presence of a nitric oxide synthase inhibitor, L‐NAME (10−4 M), a H2O2 inhibitor, PEG‐catalase (500 units/mL), or both to determine the mediator of dilation. Fluorescence microscopy using intraluminal MitoPY1 probed for H2O2 production in response to IILP.ResultsIn healthy vessels treated with ZLN, a trend toward a reduction in FID from control was observed after addition of either L‐NAME or PEG‐catalase under physiological pressure conditions (n=6–8; NS). PEG‐catalase alone reduced FID after IILP (n=7; P < 0.05), with a similar trend in unstressed vessels from patients with CAD (n=9; NS). Complete inhibition of FID was observed in PGC‐1α‐activated vessels after addition of both L‐NAME and PEG‐catalase and in vessels from subjects with CAD (n=8; P < 0.05) or without CAD under physiological pressure conditions (n=6; P < 0.05). Fluorescence data confirmed that H2O2 production persisted after IILP in healthy treated vessels.Conclusion and SignificanceIn contrast to the exclusively NO‐or H2O2‐mediated dilation seen in healthy or diseased conditions, respectively, activation of PGC‐1α with ZLN005 allows both NO and H2O2 to simultaneously contribute to dilation under basal pressure conditions and in the presence of CAD, but not after acute high pressure stress. These data provide support for the notion that dilation may be potentiated by more than one factor in the human microcirculation and that PGC‐1α may regulate plasticity in the mechanism of dilation in health and disease.Support or Funding InformationFunding support provided by R01‐HL‐113612 (to D. D. Gutterman) and T32‐GM‐08020206 [Medical Scientist Training Program Grant] (to J. T. Barbieri)