title: Effects of age on noninvasive assessments of vascular function in nonhuman primates: implications for translational drug discovery.
abstract: BACKGROUND
  Endothelium-dependent flow mediated dilation (FMD) and pulse-wave velocity (PWV), are used as measures of vascular health and predictors of cardiovascular risk in clinical studies, and both are age-dependent. Numbers of circulating endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are also associated with cardiovascular risk, but independent of age in humans. The use of these measurements for pre-clinical assessment of drug cardiovascular safety and efficacy in non-human primates (NHPs) may promote the translation of drug-induced effects on vascular function to clinic outcomes. However, in NHPs, the age effects on the non-invasive measurements of FMD and PWV and the relationship of EMPs/EPCs with FMD are unknown.
  
  
  METHODS
  A non-invasive, clinically-relevant approach to assess FMD and PWV was used to examine their relationship with age and with EMPs/EPCs in NHPs. The effects on FMD of nicotine and rosiglitazone were evaluated in senescent primates in an effort to validate our FMD method for pre-clinical assessment of vascular function.
  
  
  RESULTS
  FMD and PWV methods were established in a colony (n = 25) of metabolically healthy, cynomolgus monkeys ranging in age from 6 to 26 years. FMD, defined as the percent change, at 1 min of cuff release, from baseline vascular diameter (0.15 ± 0.03 cm), had a strong, negative correlation with age (r = -0.892, p < 0.0001), ranging from 6% to 33%. PWV positively correlated with age (r = 0.622, p < 0.002) in the same healthy monkeys. Nicotine and rosiglitazone, were evaluated in subsets of senescent primates (mean age 16.3 ± 1.5[SEM] years). Rosiglitazone significantly improved FMD (21.0 ± 1.6% vs. vehicle 16.3 ± 1.6%, p < 0.01) without changing baseline diameters, and coincided with a significant increase in circulating numbers of endothelial progenitor cells (CD45-CD31 + CD34 + VEGFR2+ 7.1 ± 1.3 vs. 4.8 ± 1.1 counts/μl) and a decrease in endothelial microparticles (CD45-CD42a-CD54+ 26.7 ± 11.1 vs. 62.2 ± 9.8 counts/μl)(p < 0.05). Conversely, FMD was significantly reduced with nicotine (8.7 ± 1.4% vs. vehicle 20.1 ± 2.2%, p < 0.05).
  
  
  CONCLUSIONS
  Adult NHPs demonstrate the characteristic linear relationship between age and vascular function using the non-invasive clinically-related measurements of FMD and PWV. However, numbers of circulating EMPs and EPCs did not correlate with age. Endothelial function assessed with FMD, together with EMPs/EPCs assessment, may serve as a novel approach for translational research and therapeutic discovery. Age should be considered in the study design or data analyses when FMD or PWV is used in NHPs.
authors.affiliation: Pfizer Worldwide Research and Development, Cardiovascular and Metabolic Diseases Research Unit, Pfizer Inc, Groton, CT 06340, USA.
authors.forename: Delvin R
authors.initials: DR
authors.lastname: Knight
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Smith
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schroeder
authors.forename: Chunli
authors.initials: C
authors.lastname: Huang
authors.forename: David A
authors.initials: DA
authors.lastname: Beebe
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Sokolowski
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
mesh_terms: D000367:Age Factors; D000818:Animals; D001916:Brachial Artery / Q000473:pathology; D055808:Drug Discovery; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D005263:Femoral Artery / Q000473:pathology; D005951:Glucose Tolerance Test; D008070:Lipopolysaccharides / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D000077154:Rosiglitazone; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D057170:Translational Research, Biomedical
chemical_list: D008070:Lipopolysaccharides; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009538:Nicotine