Determinants of Flow-Mediated Outward Remodeling in Female Rodents

Abstract

Objective-Flow (shear stress)-mediated outward remodeling (FMR) of resistance arteries is a key adaptive process allowing collateral growth after arterial occlusion but declining with age. 17-β-estradiol (E2) has a key role in this process through activation of estrogen receptor α (ERα). Thus, we investigated the impact of age and timing for estrogen efficacy on FMR. Approach and Results-Female rats, 3 to 18 months old, were submitted to surgery to increase blood flow locally in 1 mesenteric artery in vivo. High-flow and normal-flow arteries were collected 2 weeks later for in vitro analysis. Diameter increased by 27% in high-flow arteries compared with normal-flow arteries in 3-month-old rats. The amplitude of remodeling declined with age (12% in 18-month-old rats) in parallel with E2 blood level and E2 substitution failed restoring remodeling in 18-month-old rats. Ovariectomy of 3-, 9-, and 12-month-old rats abolished FMR, which was restored by immediate E2 replacement. Nevertheless, this effect of E2 was absent 9 months after ovariectomy. In this latter group, ERα and endothelial nitric oxide synthase expression were reduced by half compared with age-matched rats recently ovariectomized. FMR did not occur in ERα −/− mice, whereas it was decreased by 50% in ERα +/− mice, emphasizing the importance of gene dosage in high-flow remodeling. Conclusions-E2 deprivation, rather than age, leads to decline in FMR, which can be prevented by early exogenous E2.However, delayed E2 replacement was ineffective on FMR, underlining the importance of timing of this estrogen action. 15 The initial results suggested a negative impact of the treatment, leading to a worldwide reduction in the use of substitution therapies. Nevertheless, recent publications with a more detailed analysis of the data countermanded the initial conclusion. Interestingly, a major difference in the effect of hormones between younger and older women has been shown. Indeed, the treatment tended to confer coronary protection in women treated within 10 years after menopause, whereas a latter treatment may induce deleterious effects. 24 The mechanisms accounting for the impact of timing in the atheroprotective action of estrogens has been recently reviewed. 15 In particular, it has been described, in the atheroma plaque, a decreased ERα expression 16,25 and an increase in 27-hydroxycholesterol (27HC) production. 26 Indeed, 27HC is a competitive antagonist of ER action, which can counteract the protective action of 17-β-estradiol (E2). 26To better understand to which extent a timing effect also can impact the function of arterioles, we investigated FMR of resistance arteries in young and old female rats and then in young ovariectomized rats as a model of surgical menopause. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Estradiol Blood Level and FMRFourteen days after arterial ligation, arterial diameter was determined in vitro in response to stepwise increases in intraluminal pressure. Passive arterial diamet...

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

“…It contributes to the prevention of further tissue injury (eg, in limb or myocardial ischemia). FMR has been shown to be reduced by hypertension,58, 59 diabetes mellitus,60, 61 and aging 11, 62. More important and rather unexpectedly, we previously reported that FMR depends on the presence of ERα15, 63 and could contribute to the better resistance to ischemia/necrosis of female compared with male mice.…”

“…In particular, 17β‐estradiol strongly prevents lipid deposition in mouse models of atherosclerosis: apolipoprotein E–deficient6, 7 and low‐density lipoprotein receptor–deficient (LDLr −/− )8 mice. In addition, in several experimental models of hypertension, ovariectomy exacerbates, whereas estrogen replacement attenuates, the course of hypertension9, 10 and reduces arterial stiffening associated with hypertension or aging 11. 17β‐estradiol also increases basal nitric oxide (NO) production,12 accelerates reendothelialization,8, 13 and prevents postinjury medial as well as neointimal hyperplasia after vessel injury 14.…”

“…17β‐estradiol also increases basal nitric oxide (NO) production,12 accelerates reendothelialization,8, 13 and prevents postinjury medial as well as neointimal hyperplasia after vessel injury 14. Finally, 17β‐estradiol plays a crucial role in the ability of resistance arteries to remodel in response to a long‐term increase in blood flow, which is necessary to optimize tissue perfusion 11, 15…”

Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol

“…Studies in nonhuman primates and other animal species have shown that estrogen therapy prevents atherosclerosis when therapy is initiated at the time of menopause but not when it is initiated some time later. 3,25,26 …”

Endothelium

“…41 Flowdependent outward remodeling of resistance arteries is a key adaptive process declining with age. Tarhouni et al 42 demonstrate that estrogen deprivation rather than age impairs flow mediated remodeling and that timing for estrogen replacement is important to improve this response.…”