Our findings suggest that a decline in endothelial function begins during the early stages of menopause (perimenopause) and worsens with the loss of ovarian function and prolonged estrogen deficiency. These data add to the accumulating evidence that the perimenopausal window is a critical time period for adverse changes in CVD risk.

T supplementation was well tolerated and improved body composition but had no effect on functional performance. T supplementation improved upper body strength only in nonexercisers compared with placebo.

Vascular aging, featuring endothelial dysfunction and large artery stiffening, is a major risk factor for developing cardiovascular disease (CVD). In women, vascular aging appears to be accelerated during the menopause transition, particularly around the late perimenopausal period, presumably related to declines in ovarian function and estrogen levels. The mechanisms underlying endothelial dysfunction and large artery stiffening with the menopause transition are not completely understood. Oxidative stress and the proinflammatory cytokine tumor necrosis factor-α contribute to endothelial dysfunction and large artery stiffening in estrogen-deficient postmenopausal women. Habitual endurance exercise attenuates the age-related increase in large artery stiffness in estrogen-deficient postmenopausal women and can reverse arterial stiffening to premenopausal levels in estrogen-replete postmenopausal women. In contrast, estrogen status appears to play a key permissive role in the adaptive response of the endothelium to habitual endurance exercise in that endothelial improvements are absent in estrogen-deficient women but present in estrogen-replete women. We review here the current state of knowledge on the biological defects underlying vascular aging across the menopause transition, with particular focus on potential mechanisms, the role of habitual exercise in preserving vascular health, and key areas for future research.

G protein-coupled receptor kinase-2 (GRK2) can phosphorylate and desensitize the platelet-derived growth factor receptor-␤ (PDGFR␤) in heterologous cellular systems. To determine whether GRK2 regulates the PDGFR␤ in physiologic systems, we examined PDGFR␤ signaling in mouse embryonic fibroblasts from GRK2-null and cognate wild type mice. To discern a mechanism by which GRK2-mediated phosphorylation can desensitize the PDGFR␤, but not the epidermal growth factor receptor (EGFR), we investigated effects of GRK2-mediated phosphorylation on the association of the PDGFR␤ with the Na ؉ /H ؉ exchanger regulatory factor (NHERF), a protein shown to potentiate dimerization of the PDGFR␤, but not the EGFR. Physiologic expression of GRK2 diminished (a) phosphoinositide hydrolysis elicited through the PDGFR␤ but not heterotrimeric G proteins; (b) Akt activation evoked by the PDGFR␤ but not the EGFR; and (c) PDGF-induced tyrosyl phosphorylation of the PDGFR␤ itself. PDGFR␤ desensitization by physiologically expressed GRK2 correlated with a 2.5-fold increase in PDGF-promoted PDGFR␤ seryl phosphorylation. In 293 cells, GRK2 overexpression reduced PDGFR␤/ NHERF association by 60%. This effect was reproduced by S1104D mutation of the PDGFR␤, which also diminished PDGFR␤ activation and signaling (like the S1104A mutation) to an extent equivalent to that achieved by GRK2-mediated PDGFR␤ phosphorylation. GRK2 overexpression desensitized only the wild type but not the S1104A PDGFR␤. We conclude that GRK2-mediated PDGFR␤ seryl phosphorylation plays an important role in desensitizing the PDGFR␤ in physiologic systems. Furthermore, this desensitization appears to involve GRK2-mediated phosphorylation of PDGFR␤ Ser 1104

Large elastic arterial stiffening and endothelial dysfunction are phenotypic characteristics of vascular aging, a major risk factor for age-associated cardiovascular diseases. Compared to men, vascular aging in women appears to be slowed until menopause, whereafter vascular aging accelerates to match that seen in men. These sex differences in vascular aging have been attributed to changes in sex hormones that occur with aging. Although the role of estradiol in vascular aging in women has been highlighted in recent aging research, little is known about the impact of declining testosterone concentrations in both sexes. Importantly, while androgen concentrations generally decline with age in men, there are data that indicate reductions in androgen concentrations in women as well. Evidence suggests that low testosterone is associated with impaired endothelial function and increased arterial stiffness in men, although the effect of androgens on vascular aging in women remains unclear. Testosterone may modulate vascular aging by mitigating the effects of oxidative stress and inflammation, although there is sex specificity to this effect. The purpose of this review is to present and summarize the research regarding sex differences in vascular aging in response to androgens, specifically testosterone. Because exercise is a potent lifestyle factor for slowing and reversing vascular aging, we briefly summarize the available literature regarding the regulatory function of testosterone on vascular adaptations to exercise training.