Estrogen inhibits the response-to-injury in a mouse carotid artery model.

Background-We hypothesized that estrogen-induced acceleration of reendothelialization might be mediated in part by effects involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells (EPCs). Methods and Results-Carotid injury was induced in ovariectomized wild-type mice receiving either 17␤-estradiol or placebo. Estradiol treatment significantly accelerated reendothelialization of injured arterial segments within 7 days and resulted in a significant reduction of medial thickness 14 and 21 days after the injury. Significant increases in circulating EPCs 3 days after the injury were observed in the estradiol group compared with placebo-treated mice. These data were further supported by fluorescence-activated cell sorting analysis, which disclosed a significant increase in Sca-1/Flk-1-positive cells in estradiol versus control mice. To evaluate the effects of estradiol on bone marrow-derived EPC incorporation at sites of reendothelialization, carotid injury was established in ovariectomized wild-type mice transplanted with bone marrow from transgenic donors expressing ␤-galactosidase transcriptionally regulated by the Tie-2 promoter. Significantly greater numbers of X-gal-positive cells were observed at reendothelialized areas in the estradiol group 3 days after injury as compared with placebo. Fluorescent immunohistochemistry 14 days after the injury documented a marked increase in cells expressing both ␤-gal, indicating bone marrow origin and Tie-2 expression, and isolectin B4, also indicating endothelial lineage, in the estradiol group compared with control. In contrast, estradiol did not accelerate reendothelialization or augment EPC mobilization into the peripheral circulation after injury in endothelial nitric oxide synthase-deficient mice (eNOS Ϫ/Ϫ ). Furthermore, estradiol exhibited direct stimulatory effects on EPC mitogenic and migration activity and inhibited EPC apoptosis. Conclusions-Estradiol

show abstract

“…Also consistent with prior studies, estradiol significantly inhibited the injury-induced increase in medial area ( Figure 1, C and D). 28 …”

Section: Resultsmentioning

confidence: 99%

Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Using a mouse model of carotid arterial injury, Mendelsohn and his collaborators have shown that E 2 administration completely inhibits the vascular injury response in ovariectomized WT and ER␣-Neo KO (␣ERKO in ref. 12) mice (13,24). At the time, these observations were interpreted as indicating that estrogen inhibits the vascular injury response by an ER␣-independent pathway and therefore suggested that ER␤ could mediate the protective effects of E 2 on the vasculature.…”

Section: Discussionmentioning

confidence: 99%

The AF-1 activation-function of ERα may be dispensable to mediate the effect of estradiol on endothelial NO production in mice

Pendaries

Darblade

Rochaix

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

159

View full text Add to dashboard Cite

Two isoforms of estrogen receptor (ER) have been described: ER␣ and ER␤. The initial gene targeting of ER␣, consisting in the introduction of a Neo cassette in exon 1 [␣ERKO, hereafter called ER␣-Neo KO (knockout)], was reported in 1993. More recently, another mouse deficient in ER␣ because of the deletion of exon 2 (ER␣KO, hereafter called ER␣-⌬2 KO) was generated. In ovariectomized ER␣-wild-type mice, estradiol (E2) increases uterine weight and basal production of endothelial nitric oxide (NO). Both of these effects are abolished in ER␣-⌬2 KO mice. In contrast, we show here that both of these effects of E 2 are partially (uterine weight) or totally (endothelial NO production) preserved in ER␣-Neo KO. We also confirm the presence of two ER␣ mRNA splice variants in uterus and aorta from ER␣-Neo KO mice. One of them encodes a chimeric ER␣ protein (ER␣55), partially deleted in the A͞B domain, that was detected in both uterus and aorta by Western blot analysis. The other ER␣ mRNA splice variant codes for an isoform deleted for the A͞B domain (ER␣46), which was detected in uterus of ER␣-Neo KO, and wild-type mice. This protein isoform was not detected in aorta. The identification of these two N-terminal modified isoforms in uterus, and at least one of them in aorta, probably explains the persistence of the E 2 effects in ER␣-Neo KO mice. Furthermore, ER␣-Neo KO mice may help in the elucidation of the specific functions of full-length ER␣ (ER␣66) and ER␣46, both shown to be physiologically generated in vivo.

show abstract

“…A number of observational epidemiological studies have demonstrated postmenopausal estrogen replacement therapy in women can decrease the incidence of myocardial infarction and cardiac death by 35-50% [2][3][4][5][6]. These epidemiologic studies are supported further by animal studies demonstrating E2-mediated inhibition of experimentally induced atherosclerosis [7][8][9][10][11][12]46]. The atheroprotectix e effects of E2 are generally believed to be mediated in part b3 effects of E2 on systemic factors such as serum lipid levels [2.13,14].…”

Section: Introductionmentioning

confidence: 99%