HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI–dependent manner

Abstract

Cardiovascular diseases remain the leading cause of death in the United States. Two factors associated with a decreased risk of developing cardiovascular disease are elevated HDL levels and sexspecifically, a decreased risk is found in premenopausal women. HDL and estrogen stimulate eNOS and the production of nitric oxide, which has numerous protective effects in the vascular system including vasodilation, antiadhesion, and anti-inflammatory effects. We tested the hypothesis that HDL binds to its receptor, scavenger receptor class B type I (SR-BI), and delivers estrogen to eNOS, thereby stimulating the enzyme. HDL isolated from women stimulated eNOS, whereas HDL isolated from men had minimal activity. Studies with ovariectomized and ovariectomized/estrogen replacement mouse models demonstrated that HDL-associated estradiol stimulation of eNOS is SR-BI dependent. Furthermore, female HDL, but not male HDL, promoted the relaxation of muscle strips isolated from C57BL/6 mice but not SR-BI null mice. Finally, HDL isolated from premenopausal women or postmenopausal women receiving estradiol replacement therapy stimulated eNOS, whereas HDL isolated from postmenopausal women did not stimulate eNOS. We conclude that HDL-associated estrodial is capable of the stimulating eNOS. These studies establish a new paradigm for examining the cardiovascular effects of HDL and estrogen.

HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3

“…In a different study, the same authors showed that female but not male HDL activated eNOS and promoted vasodilation, which they attributed to HDL-associated estradiol (50). In our study, we did not observe any differences in the vasodilatory effect between male and female HDL, and there was no gender difference in the S1P content.…”

“…As with HDL, the vasorelaxing effect was completely absent in aortae from eNOS -/-mice ( Figure 3c). All three lysophospholipids (SPC, S1P, LSF) induced a dose-dependent vasodilation in isolated aortae with a similar EC 50 [-log/mol] (SPC = 7.7 ± 0.1; S1P = 7.6 ± 0.4 ; LSF = 7.5 ± 0.1) (Figure 3d). …”

Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor–BI mediate HDL-initiated signaling

“…Furthermore, cholesterol-free Lp2A-I particles caused eNOS activation, whereas cholesterol-containing Lp2A-I did not. These findings also indicate that minor components of HDL, namely estrogen and sphingosine-1-phosphate (S1P), which have been previously implicated in eNOS activation (35,36), are most likely minimally involved in this pathway. This conclusion is consistent with the observations that HDL activates eNOS in cells devoid of estrogen receptors (14) and that it stimulates myocardial perfusion in mice deficient for the S1P receptor S1P 3 (34).…”

“…These agents were prepared as previously described (13,(16)(17)(18). Of note, Gong and colleagues reported that HDL isolated from female humans or mice has greater capacity to stimulate eNOS than does HDL from male humans or mice, which suggests a role for estradiol associated with HDL (35). However, HDL-mediated responses were apparent at lipoprotein concentrations that would provide estradiol at levels as low as 5 × 10 -16 M (35), which is 6 orders of magnitude lower than the concentration shown to activate eNOS in prior reports (52,53), and Nofer and colleagues more recently found no difference in responses to male-versus female-derived HDL (36).…”

HDL action on the vascular wall: is the answer NO?

“…Previous work by Gong and coworkers suggests that another potential cargo of HDL, namely estradiol, plays a role in eNOS activation by the lipoprotein (19). They reported that HDL isolated from female humans or mice had greater capacity to stimulate the enzyme than did HDL from male humans or mice.…”