Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

Abstract

tance arteries, a chronic increase in blood flow induces hypertrophic outward remodeling. This flow-mediated remodeling (FMR) is absent in male rats aged 10 mo and more. As FMR depends on estrogens in 3-mo-old female rats, we hypothesized that it might be preserved in 12-mo-old female rats. Blood flow was increased in vivo in mesenteric resistance arteries after ligation of the side arteries in 3-and 12-mo-old male and female rats. After 2 wk, high-flow (HF) and normal-flow (NF) arteries were isolated for in vitro analysis. Arterial diameter and cross-sectional area increased in HF arteries compared with NF arteries in 3-mo-old male and female rats. In 12-mo-old rats, diameter increased only in female rats. Endothelial nitric oxide synthase expression and endothelium-mediated relaxation were higher in HF arteries than in NF arteries in all groups. ERK1/2 phosphorylation, NADPH oxidase subunit expression levels, and arterial contractility to KCl and to phenylephrine were greater in HF vessels than in NF vessels in 12-mo-old male rats only. Ovariectomy in 12-mo-old female rats induced a similar pattern with an increased contractility without diameter increase in HF arteries. Treatment of 12-mo-old male rats and ovariectomized female rats with hydralazine, the antioxidant tempol, or the angiotensin II type 1 receptor blocker candesartan restored HF remodeling and normalized arterial contractility in HF vessels. Thus, we found that FMR of resistance arteries remains efficient in 12-mo-old female rats compared with age-matched male rats. A balance between estrogens and vascular contractility might preserve FMR in mature female rats. microcirculation; remodeling; blood flow; shear stress; sex; aging; estrogen RESISTANCE ARTERIES control local blood flow to organs. They are able to adapt in response to changes in hemodynamic conditions, even in the adult. A chronic increase in blood flow (shear stress) in these vessels induces outward hypertrophic remodeling associated with increased endothelium [nitric oxide (NO)]-dependent dilation, as shown in male (2,5, 33) and female rats (37). Chronic increases in blood flow occur in physiological conditions such as growth, chronic exercise, or pregnancy as well as in ischemic disorders, where they contribute to collateral arteries growth (7, 36). Flowmediated outward remodeling of resistance arteries involves a transient inflammatory response (1) and oxidative stress (2) that favors the formation of peroxinitrite, which then activates metalloproteinases and extracellular matrix digestion (2,8,14,16,19). The final step, leading to diameter enlargement, requires a dilator stimulus (17). Flow-mediated outward remodeling is also associated with a compensatory increase in wall mass (11, 32) due to ANG II type 1 receptor activation of ERK1/2 (11).As shown in male rats, flow-mediated remodeling of mesenteric resistance arteries does not occur in male rats aged 12 mo (40) or 24 mo (15). Although no diameter enlargement occurred in arteries after increasing blood flow, endotheliummedia...

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

“…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. Herein, we report that ERα MISS is also dispensable to mediate this beneficial action of estrogens.…”

Microvascular NADPH oxidase in health and disease

“…For example, mRNA transcript and protein of Nox1, Nox2, Nox4, p22 phox , p47 phox , p67 phox and Rac1/2 subunits were detected in mouse and rat mesenteric resistance arteries [19,58,60,66,67,71], where Noxs are implicated in structural and functional alterations in response to distinct stimuli [17,72,73]. In mouse coronary arteries, protein expression of Nox2 and its regulatory subunits p67 phox , p47 phox and p22 phox were reported [64].…”

Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose

“…Estrogens exert beneficial effects on the vasculature [ 25 ] and flow-mediated remodeling of mesenteric resistance arteries dependent on the activation of the estrogen receptor alpha by estrogens [ 18 , 26 , 27 ]. Although women are better protected than men against cardiovascular diseases before menopause [ 28 ], the WHI study led to the interruption of estrogen substitution treatments in post-menopausal women [ 28 ].…”

“…The ability of resistance arteries to enlarge their diameter in response to a chronic increase in blood flow in vivo is strongly reduced in rat models of aging [ 16 – 18 ], hypertension [ 19 , 20 ] and diabetes [ 11 , 21 , 22 ] although maintained in obesity [ 23 ]. Flow-mediated outward remodeling does not occur in male rats aged 10 months or more [ 16 , 17 , 24 , 25 ] whereas it is maintained in female rats aged 12 to 18 months [ 26 ].…”