Publisher's Synopsis
Postmenopausal women (PMW) exhibit reduced endothelial function
compared to younger, premenopausal women (YW). This is mainly attributed to the
loss of estrogen with menopause but the mechanisms underlying the decline in
endothelial function remain unclear. Angiotensin-(1-7) [Ang-(1-7)] induces
vasodilation through the Mas receptor (MasR) and has been shown to restore
endothelium-dependent dilation in women with endothelial dysfunction. Animal
studies suggest menopause and aging reduce vascular sensitivity to Ang-(1-7) which
may cause a compensatory upregulation of MasR. However, the role of the Ang-(1-7)/
MasR axis has not yet been studied in humans. The central hypothesis of this was
that the Ang-(1-7)/MasR axis is a main regulator of vascular function in women and
that there is dysfunction in this pathway that occurs during menopause which leads to
the pathologies associated with the onset of CVD. We hypothesize that PMW would
have decreased vascular sensitivity to Ang-(1-7), local administration of Ang-(1-7)
would improve endothelial function, and PMW would show a compensatory-based
upregulation of MasR on endothelial cells. Methods: Blood flow was measured using
laser Doppler flowmetry. To assess vascular sensitivity, Ang-(1-7) was locally
administered in escalating doses in the presence and absence of L-NAME via
cutaneous microdialysis to elicit a dose-dependent response. Dose response curves
were fit to a sigmoidal curve and the ED50, slope, area under the curve, and peak
response were compared between groups. To assess endothelial function, local
heating of the cutaneous circulation to 42C - which elicits an endothelium-dependent dilation - was performed during microdialysis perfusions of
lactated Ringers (control) or Ang-(1-7). All skin blood flow data are expressed as
cutaneous vascular conductance as a percentage of the maximum dilation elicited by
sodium nitroprusside perfusions with heating to 43����C (CVC%max). Separately,
venous endothelial cells were collected from PMW and YW and stained for MasR
using immunocytochemistry and are expressed as protein expression arbitrary units
(A.U.) following normalization to a positive control. All data are presented as
mean+SD and alpha was set to P
older than YW and showed elevated diastolic blood pressure, total cholesterol, LDL
cholesterol, HDL cholesterol, and blood glucose that is characteristic with aging and
menopause in this population. There were no differences in the dose-dependent
response to Ang-(1-7) (Top: (YW: 99.93+17.32 vs. PMW: 97.58+31.32), LogED50
(YW: 9.34+10.5 vs PMW: 8.40+3.96), HillSlope (YW: 0.18+0.24 vs PMW:
0.25+0.21), or area under the curve (YW: 73.76+19.83, vs PMW: 67.35+12.01);
p>0.05 for all variables). There was also no significant difference in NO-dependent
dilation to Ang-(1-7) between YW and PMW (YW: 7.56+26.36 AUC vs. PMW:
17.40+25.75 AUC; p=0.48). PMW displayed a blunted endothelial function shown by
a significantly attenuated response to local heating in the control site (YW: 91.26+4.87
CVC%max vs. PMW: 85.97+5.63 CVC%max; p=0.03), however, there was no impact of
Ang-(1-7) on the response to local heating in either group (YW: 89.23+10.35
CVC%max vs. PMW 87.19+9.57 CVC%max; p=0.88). Lastly, there were no differences
in endothelial MasR expression between groups (YW: 0.36+0.08 A.U
