Vascular endothelial adiponectin signaling across the life span

Abstract

Cardiovascular disease risk increases with age regardless of sex. Some of this risk is attributable to alterations in natural hormones throughout the life span. The quintessential example of this being the dramatic increase in cardiovascular disease following the transition to menopause. Plasma levels of adiponectin, a "cardioprotective" adipokine released primarily by adipose tissue and regulated by hormones, also fluctuate throughout one's life. Plasma adiponectin levels increase with age in both men and women, with higher levels in both pre- and postmenopausal women compared with men. Younger cohorts seem to confer cardioprotective benefits from increased adiponectin levels yet elevated levels in the elderly and those with existing heart disease are associated with poor cardiovascular outcomes. Here, we review the most recent data regarding adiponectin signaling in the vasculature, highlight the differences observed between the sexes, and shed light on the apparent paradox regarding increased cardiovascular disease risk despite rising plasma adiponectin levels over time.

Keywords: adiponectin; age; sex; vascular.

Figure 1.

Plasma adiponectin and cardiovascular (CVD) risk over time. A: both low and high levels of plasma adiponectin are associated with CVD risk and mortality. B: time course of plasma adiponectin levels in both women and men over the life span. Adiponectin levels increase in women at puberty and decrease during the transition to menopause before rising again postmenopause. Men experience a decrease in plasma adiponectin at puberty that recovers over time; however, levels are lower compared with women.

Figure 2.

The estrogen-adiponectin paradox in aging females. Plasma estrogen levels decline while adiponectin levels increase during the transition to menopause. T-cadherin is critical for the binding of adiponectin to adiponectin receptor (AdipoR) 1/2. Once receptors are activated, the adapter protein AAPL1 is required to activate various downstream pathways, including AMPK and PI3K/Akt, which results in an increase in endothelial nitric oxide (NO) synthase (eNOS)-generated NO. Activation of AdipoR1/2 dramatically increases hydrolysis of ceramide (Cer), a sphingolipid that induces endothelial dysfunction. The NO-generating pathways combined with shifting the sphingolipid rheostat toward sphingosine (Sph)-1-phosphate (S1P) promotes a healthy endothelium. Despite the rise in adiponectin during menopause, women have an elevated risk of cardiovascular disease, which may be due to dysfunctional T-cadherin, AdipoR1/2, and/or APPL1 signaling (gray). Both the loss of NO-stimulating pathways and decrease in AdipoR1/2 ceramidase activity contributes to decreased NO bioavailability and endothelial dysfunction.