Mechanisms and regulation of NO-dependent endothelial dysfunction : in vivo assessment through analysis of blood pressure variability
(2007)
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- Authors
- Supervisors
- Balligand, Jean-Luc
- Abstract
- Despite a gradual and continuous decrease of the mortality of cardiovascular diseases, they are still nevertheless the most important cause of death in Europe and North America. It remains thus essential to study and to understand the pathophysiological mechanisms involved in the evolution of the disease, notably endothelial dysfunction development, which is largely responsible for the initiation of atherosclerosis and other cardiovascular complications. In the first part of this thesis, we describe a validation of spectral analysis of systolic blood pressure variability, acquired through chronically implanted telemetry in mice, as a quantitative assay of NO bioactivity in the vasculature in vivo. The technique of telemetry allows accurate and reliable continuous recordings in conscious and unrestrained animals compared to other methods of assessment such as tail-cuff technique. There is only limited experience with frequency analysis of blood pressure tracings in mice, and no previous characterization of wavelengths reflecting the effects of endogenous NO. We provide this characterization and isolate the effect of NO from indirect influences of absolute blood pressure levels or circulating neurohormones. We believe this index of blood pressure variability, using wavelengths as described here, will provide the scientific community with a new tool to study the effects of genetic, molecular or pharmacologic interventions on NO-dependent endothelial function in numerous mouse models of human cardiovascular diseases. Secondly, we used this quantitative analysis of NO bioavailability to the phenotypic characterization of mice with homozygous deletion of caveolin-1 (cav-1), a critical allosteric regulator of the endothelial NO synthase, as well as a mouse model of endothelial dysfunction, thereby adding original results both demonstrating the applicability of our analysis to mouse pathophysiologic models and extending current understanding on the role of caveolins in cardiovascular regulation in vivo. Indeed, the cav-1 knockout mouse model has validated the functional importance of cav-1 on the production of bioactive NO and its control of blood pressure variability. We showed that increased circulating Hb-NO in vivo, vessel relaxation and NO production ex vivo in cav-1-/- mice resulted in decreased variability in specific bandwidths reflecting NO ¡§buffering¡¨ of SBP. Furthermore, we also used a mouse model of endothelial dysfunction, the apolipoprotein E deficient mice, to confirm the applicability of our analysis to mice pathophysiologic models. Finally, we apply this index of blood pressure variability on a pathophysiological mouse model of the metabolic syndrome (mice genetically deficient in both leptin and the LDL receptor). We studied the effect of a statin treatment on components of blood pressure regulation in these obese mice. In rosuvastatin-treated mice, we observed full normalization of blood pressure, its circadian variation and short-term variability (a prognostic index for cardiovascular morbidity), together with improved NO-dependent blood pressure control. Importantly, this was observed despite incomplete correction of insulinoresistance and no effect on weight gain nor significant reduction of cholesterol. Notably, this was associated with induction of the expression of PPARg in the vascular wall; moreover, this was reproduced in isolated endothelial cells in which the statin induced upregulation of SOD1 in a PPAR-dependent manner. Indeed, both GW9662, a PPARg-specific antagonist, and cell transfection with siRNA raised against PPAR × nabrogated the upregulation of SOD1 in response to rosuvastatin. This was reproduced in PPARa- (but not PPARg-) dependent transactivation assays, thus demonstrating the causal involvement of PPARg in the upregulation of SOD1 expression. These observations, we think, add to the understanding of vasculoprotective effects of statins in the metabolic syndrome, in part independent from cholesterol lowering, changes in weight or glucose tolerance, as suggested (for the latter) from the recent analysis of the TNT trial in patients with this syndrome.1
- Affiliations
Citations
Desjardins, F. (2007). Mechanisms and regulation of NO-dependent endothelial dysfunction : in vivo assessment through analysis of blood pressure variability. https://hdl.handle.net/2078.5/112079