Articles

Estrogen-Induced Alterations in Lipoprotein Metabolism in Autoimmune MRL/lpr Mice

Steven H. Zuckerman, Nancy Bryan-Poole
https://doi.org/10.1161/01.ATV.15.10.1556
Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1556-1562
Originally published October 1, 1995

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Abstract

Abstract Estrogen replacement therapy has been demonstrated to shift the lipoprotein profile toward a less atherogenic one with concomitant increases in HDL and reductions in LDL cholesterol and serum triglycerides. Estrogen, however, has also been implicated in playing a significant role in autoimmune disease and may be involved with disease incidence and progression. The MRL/lpr mouse strain represents an autoimmune disease model with features resembling systemic lupus erythematosus including high-titer autoantibodies, glomerulonephritis, and vasculitis. In the present study, the effects of estrogen treatment on serum lipoprotein profiles were investigated by fast protein liquid chromatography in female MRL/lpr mice, in the MRL/++ strain with a milder form of disease, and in control Balb/c mice. Treatment of MRL/lpr mice for periods of 1 week or longer with pharmacologic doses of estrogen resulted in a significant increase in the amount of cholesterol carried on LDL particles. The up to eightfold increase in LDL cholesterol was less significant in the MRL/++ or Balb/c mice. Maximal increases were observed at 1 to 2 mg/kg of estrogen agonists, and the effect on LDL cholesterol increases was inhibited by tamoxifen. The HDL-to-LDL shift in cholesterol observed in estrogen-treated autoimmune mice correlated with an increase in apolipoprotein E, primarily on larger HDL particles. In addition to the increase in LDL cholesterol, hormonal treatment also resulted in a shift in triglycerides from the VLDL to the LDL fraction in both normal and autoimmune mice. These results suggest that pharmacologic doses of estrogen may contribute to cardiovascular disease progression by shifting the relative distribution of cholesterol from HDL to LDL in this murine model of lupus.

  • Received May 18, 1995.
  • Accepted August 2, 1995.

Estrogen replacement therapy has been demonstrated to be associated with a reduction in cardiovascular disease in postmenopausal women.1 2 3 The effects of oral estrogen treatment on decreasing cardiovascular disease are most likely related to its pleiotropic effects on lipoproteins, apoproteins, lipoprotein receptors, and enzymes involved in lipoprotein remodeling, including lipoprotein lipase and hepatic lipase.4 5 6 Estrogenic effects on lipoprotein metabolism include increases in hepatic LDL receptors and in the amount of HDL-associated cholesterol, decreases in lipoprotein (a), and an overall increase in the rate of LDL catabolism.7 8 9 10 11 12 In addition, the effects of estrogen on endothelial cell adhesion molecules,13 14 a protective, potential antioxidant activity toward lipoproteins,15 16 and more distal effects such as regulation of cytokine gene expression and immune cell function17 18 19 20 21 22 represent other mechanisms by which estrogen could mitigate adverse cardiovascular events.

Although the beneficial effects of estrogen have been amply documented in animal models,8 9 10 11 12 there are examples in which estrogen treatment was associated with less favorable shifts in the lipoprotein profile. Mice exposed to dietary estradiol exhibited an ≈40% increase in total serum cholesterol that was diet dependent.23 High-dose estrogen, for example, has been reported to induce both apoB and VLDL synthesis in rats.24 25 In men, estrogen therapy for metastatic prostatic carcinoma resulted in a lowering of LDL cholesterol but also generated LDL particles with lower affinity for LDL receptors.26 Premenopausal women on estrogen therapy have been reported to have increased VLDL,5 and a further exacerbation of hypertriglyceridemia was described in women with preexisting hypertriglyceride levels.27 Clearly, the effects of estrogen on serum lipoproteins may be both positive and negative, depending on underlying disease processes.

Autoimmunity represents one condition in which estrogen treatment may have positive or negative effects on disease progression.28 Estrogen treatment in both animal models and humans ameliorates T cell–mediated autoimmune disease, including rheumatoid arthritis.29 30 31 However, estrogen treatment in murine models of systemic lupus erythematosus (SLE) has been reported to exacerbate disease.28 32 33 The increases in cardiovascular disease associated with SLE suggested that autoimmune processes, perhaps modulated by estrogen could contribute to atherogenesis. The MRL/lpr mouse represents an animal model in which certain features of SLE can be observed, including circulating immune complexes, the presence of antinuclear and anti–basement membrane antibodies, and relevant target pathology such as glomerulonephritis and vasculitis.34 In addition, immunosuppressive therapy in the MRL/lpr mouse mitigates disease progression, as has also been observed in SLE.35 36 The increased incidence and severity of disease in female or castrated male MRL mice suggested a role for estrogen in the modulation of disease severity.32 33 However, although the lipoprotein profile for MRL/lpr mice has been described for animals on both normal and atherogenic diets,37 , the effects of estrogen on modulating serum lipoproteins have not been previously reported.

In the present study, the changes in serum lipoproteins in MRL/lpr females after oral or subcutaneous administration of estrogen agonists have been investigated by fast protein liquid chromatography (FPLC). Whereas MRL mice have HDL as the major cholesterol-carrying particle, as do other mouse strains, estrogen treatment resulted in a significant increase in LDL cholesterol. The shift in the relative ratio of cholesterol transported by the LDL versus the HDL fraction was both time and dose dependent. The increase in LDL cholesterol was apparent with 17α-ethinyl estradiol oral dosing or by pellet implants of 17β-estradiol, estrone, or estriol. Estriol effects were the most significant, with the greatest effects at high (2 mg/kg) doses of the estrogen analogs. However, the increase in LDL cholesterol was blocked by the estrogen antagonist tamoxifen. The effects of estrogen treatment on the lipoprotein profile of the MRL/++ strain, associated with milder disease, or on normal Balb/c mice demonstrated only a modest increase in LDL cholesterol. These results suggest that, although estrogen replacement therapy is generally considered to have protective effects against cardiovascular disease, its effects in certain autoimmune disorders may contribute to cardiovascular complications.

Methods

Animal Model

Female MRL/lpr, MRL/++, and Balb/c mice were obtained from Charles River Laboratories, Portage, Mich, and were used generally between 8 and 22 weeks of age. All animals were maintained on standard mouse chow diet (Purina). Oral dosing of 17α-ethinyl estradiol in β-cyclodextrin vehicle was performed for periods of between 1 and 14 weeks. Pellets containing 17β-estradiol, estrone, or estriol (Innovative Research of America) resulting in a sustained dose of 2.2 mg/kg per day over a 3-week period were implanted subcutaneously and compared with the appropriate placebo pellet implants. Tamoxifen and 17α-ethinyl estradiol (Sigma Chemical Co) were dosed orally as a single preparation. At designated intervals mice were killed, and sera were fractionated by FPLC or evaluated for antibody titer against double-stranded DNA. All animal experiments were performed in accordance with institutional guidelines.

Serum Lipoprotein Analysis

Sera from 3 to 4 mice per group were pooled, and a 250-μL aliquot was resolved by FPLC (Pharmacia) using tandem-linked Superose 6 columns (Pharmacia) with 150 mmol/L NaCl, 1 mmol/L EDTA, and 0.02% sodium azide, pH 8.2, as the column buffer.38 Fractions (0.5 mL) were collected after disposal of the first 12 mL of void volume and assayed for total cholesterol. Total cholesterol was quantitated enzymatically from 100-μL aliquots of the FPLC fractions (Boehringer Mannheim). In select experiments triglycerides were also measured in 100-μL aliquots from the FPLC fractions by enzymatic assay (Sigma). Identification of the VLDL, LDL, and HDL peaks by FPLC were based on comigration with the appropriate human lipoprotein standards.

Electrophoresis and Immunoblot Analysis of FPLC Fractions

Sequential fractions from the LDL and HDL peaks were boiled in SDS sample buffer containing dithiothreitol and electrophoresed on 10% to 20% gradient gels. Following electrophoresis, gels were stained with Coomassie blue, and parallel gels were electroblotted, 500 mA for 40 minutes, onto nitrocellulose under semiwet blotting conditions (ABN Polyblot, American Bionetics, Inc). Nitrocellulose blots were probed with polyclonal goat antisera against human apoA-I (Calbiochem) and apoE (Chemicon). These antisera were determined in preliminary experiments to cross react with the mouse apoproteins. Detection of immunoreactive bands was by enhanced chemiluminescence, ECL (Amersham), by use of the appropriate peroxidase-conjugated secondary antibody and the procedure described by the suppliers. Film (Hyperfilm-ECL, Amersham) was exposed to the chemiluminescent signal for 5 seconds to 20 minutes depending on the primary antibody used and the resulting band intensity.

Anti-DNA ELISA

Serial dilutions of MRL sera after estradiol dosing for 3 to 14 weeks were added to double-stranded-DNA–coated plates for determination of anti-DNA titers by using established techniques. Briefly, Immulon II (Dynatech) plates were coated overnight with 100 μL of double-stranded calf thymus DNA (Sigma) at a coating concentration of 100 μg/mL in 0.02 mol/L carbonate buffer, pH 9.6. Plates were washed with PBS containing 0.05% Tween 20, blocked with PBS containing 1% dry milk for 1 hour at room temperature, and then incubated overnight with the appropriate MRL-sera dilutions at 4°C. Plates were again washed, incubated with 1/1000 dilution of peroxidase-conjugated goat anti-mouse IgG (Tago, Inc) for 90 minutes at room temperature; after subsequent washes ABTS was added as substrate, and adsorption was read at A405 on a Bio-Tek EL320 microplate reader interfaced with an IBM PC. Although sera dilutions between 1/1000 and 1/100 000 were evaluated, only the optic-density changes observed at the 1/10 000 dilution are presented, because these were in the linear range.

Statistical Analysis

Statistical analysis was performed by an unpaired (two-tailed) Student’s t test.

Results

MRL/lpr mice transport cholesterol primarily on HDL particles (Fig 1A⇓), as do other strains. The amount of LDL- and VLDL-associated cholesterol in mice fed a nonatherogenic diet was less than 15% of the total serum cholesterol. In contrast, MRL/lpr mice dosed for 3 weeks with ethinyl estradiol demonstrated a dose-dependent increase in LDL cholesterol (Fig 1B⇓ through 1D). Although the lipoprotein profile for MRL/lpr animals dosed with 0.01 mg/kg (Fig 1B⇓) was similar to that of the vehicle control (Fig 1A⇓) animals treated with 0.1 mg/kg (Fig 1C⇓) demonstrated an increase in LDL cholesterol; this increase was most apparent at the 1-mg/kg dosing protocol (Fig 1D⇓). At the high estrogen dose, the amount of LDL cholesterol was often greater than HDL cholesterol. While tamoxifen alone at 10 mg/kg had no significant effect on LDL cholesterol (data not shown), it was effective in inhibiting the increase in LDL cholesterol mediated by the ethinyl estradiol dosing regimen (Fig 1E⇓). Furthermore, the effect of 1 mg/kg ethinyl estradiol was reversible, and 1 week after cessation of estrogen treatment the amount of LDL cholesterol was significantly reduced (Fig 1F⇓). A similar estrogen-dose response in MRL/++ mice revealed a more modest increase in LDL cholesterol. The placebo-treated animals (Fig 2A⇓) demonstrated a lipoprotein profile similar to the lpr mice, with most of the cholesterol being transported on the HDL particles. In contrast to the lpr mice, a small but reproducible fraction of the serum cholesterol was associated with VLDL particles. Estrogen at 0.01 mg/kg did not result in an increase in LDL cholesterol (Fig 2B⇓), whereas an increase in LDL cholesterol was observed at 0.1 and 1 mg/kg estrogen (Fig 2C⇓ and 2D⇓). A similar increase in LDL cholesterol by 1 mg/kg estrogen for 3 weeks was also observed in Balb/c mice (Fig 3D⇓) when compared with the lipoprotein profile 24 hours after the first estrogen dose (Fig 3A⇓). Although the increase in LDL cholesterol was modest, the kinetics over a 6-week interval were examined. An increase in LDL cholesterol was reproducibly observed after 1 week of dosing (Fig 3B⇓), and this effect was more apparent by 2 weeks (Fig 3C⇓). The increase in LDL cholesterol appears to be maximal by this time-point, because extending the dosing up to 6 weeks resulted in no further increase in LDL cholesterol (Fig 3E⇓). The lipoprotein profile (not presented) for the vehicle group at each of the time points was similar to the 24-hour estrogen dose (Fig 3A⇓).

Figure 1.
Figure 1.

Graphs showing ethinyl estradiol effects on lipoprotein cholesterol in MRL/lpr mice. MRL/lpr mice were dosed orally on a daily basis with vehicle (A) or with 0.01 (B), 0.1 (C), or 1 (D) mg/kg ethinyl estradiol for 3 weeks. Additional mice were treated with tamoxifen plus 1 mg/kg ethinyl estradiol (E) or were removed from ethinyl estradiol treatment after 3 weeks and bled 1 week later (F). Sera, 250 μL, from a pool of 3 to 6 mice per treatment were resolved by FPLC, and 0.5-mL fractions were assayed for cholesterol. Shown is a representative experiment of three. Total serum cholesterol was determined from each of the FPLC pools, and values of 158, 134, 161, 234, 118, and 156 mg/dL were obtained from samples A through F, respectively.

Figure 2.
Figure 2.

Graphs showing ethinyl estradiol effects on lipoprotein cholesterol in MRL/++ mice. Mice were dosed orally with vehicle (A), 0.01 (B), 0.1 (C), or 1 (D) mg/kg ethinyl estradiol for 3 weeks. Mice from each group were killed, and sera were pooled and run on FPLC, as described in the legend to Fig 1⇑. Total serum cholesterol was determined from each of the pools, and values of 156, 157, 196, and 205 mg/dL were obtained from samples A through D, respectively.

Figure 3.
Figure 3.

Graphs showing ethinyl estradiol effects on lipoprotein cholesterol in Balb/c mice. Balb/c mice were dosed with 1 mg/kg ethinyl estradiol for 1 day (A), 1 week (B), 2 weeks (C), 3 weeks (D), and 6 weeks (E). Mice from each group were killed, and sera were pooled and run on FPLC, as described in the legend to Fig 1⇑. Total serum cholesterol values after 1 day, 3 weeks, and 6 weeks on estradiol were 98, 147, and 106 mg/dL, respectively.

Although continuous oral dosing of ethinyl estradiol resulted in shifts in the lipoprotein profile in MRL/lpr mice, there was no significant effect of estrogen in modulating the serum titer of anti-double-stranded-DNA antibodies (Fig 4⇓). The reduction in antibody titer observed in the estrogen-treated group at 21 weeks of age was less than twofold and was not observed in a second series of animals. While the antibody titer increased with the age of the animals, the extent of LDL cholesterol increase was comparable in animals from 8 to 21 weeks of age.

Figure 4.
Figure 4.

Line plot of the effects of ethinyl estradiol treatment on anti-DNA antibody titer. MRL/lpr mice were dosed with 1 mg/kg ethinyl estradiol or vehicle starting at 5 weeks of age for 3, 11, and 16 weeks. At designated ages, sera from each group were diluted in logarithmic dilutions and a 1/10 000 dilution of each sample of sera, five per group, was incubated on double-stranded-DNA–coated 96-well microtiter plates. The detection of anti-DNA antibodies was by ELISA with a peroxidase-conjugated secondary reagent. This experiment was repeated twice. Brackets indicate SD.

In additional experiments, the relative distribution of apoE and apoA-I across the lipoprotein fractions was evaluated by immunoblots. Although 9 weeks of oral dosing of MRL/lpr mice resulted in a significant increase in LDL cholesterol and shifted the ratio of LDL to HDL cholesterol to >1 (Fig 5B⇓), apoE was distributed across all the cholesterol-containing fractions, while apoA-I was restricted to the HDL region (Fig 5A⇓). There was an increase in the amount of apoE detected in the ascending portion of the HDL peak, corresponding to larger HDL particles. The shift observed in apoA-I between the placebo and estrogen treatments, however, was not a consistent observation.

Figure 5.
Figure 5.

A, Immunoblots showing apoE and apoA-I distribution in FPLC fractions. MRL/lpr mice were treated with vehicle (placebo) or 1 mg/kg ethinyl estradiol (estrogen) for 9 weeks before they were killed. Sera pools were fractionated by FPLC, and fractions were run on denaturing gradient gels. Gels were electroblotted, and nitrocellulose was probed with a primary antibody cocktail of anti-apoE and anti-apoA-I. Detection of antibody binding was by ECL. Fraction numbers are indicated. The LDL peak was located between fractions 10 and 25, and the HDL peak was between fractions 28 and 40. B, The relative cholesterol distribution between the LDL and HDL fractions was measured by quantitation of total cholesterol within each peak of the pooled FPLC fractions. Total serum cholesterol for the vehicle group was 135±14 mg//dL and for the estradiol group, 212±50 mg/dL. Values are means±SD in measuring serum cholesterol from each animal in the estrogen (n=5) and placebo (n=4) groups. The increase in serum cholesterol by estrogen was significant at a value of P<.05.

The increase in LDL cholesterol in the MRL/lpr mice was not limited to ethinyl estradiol treatment but was also apparent using other estrogen agonists administered as pellets after subcutaneous implant. Estriol at doses of 2.2 and 0.7 mg/kg increased LDL cholesterol (Fig 6A⇓ and 6B⇓) and at the lower dose of 0.15 mg/kg (Fig 6C⇓) approached the placebo lipoprotein profile (Fig 6D⇓). Implantation of 17β-estradiol (Fig 6E⇓) or estrone (Fig 6F⇓) also resulted in an increase in LDL cholesterol, although the shift in the relative ratio of LDL cholesterol to HDL cholesterol was more modest with estrone.

Figure 6.
Figure 6.

Graphs showing estrogen agonist effects on lipoprotein cholesterol distribution. MRL/lpr mice were implanted subcutaneously with estriol pellets (A through C) resulting in continuous doses of 2.2, 0.7, and 0.15 mg/kg, respectively, of estriol or 2.2 mg/kg of 17β-estradiol (E) or estrone (F). After 3 weeks of exposure mice were killed, and sera pools from each fraction were resolved by FPLC and compared with the placebo-implanted controls (D). Total serum cholesterol values from each of the FPLC pools were 171, 215, 159, 124, 155, and 122 mg/dL, respectively.

In addition to the shift in cholesterol from HDL to LDL particles, triglycerides also appeared redistributed from VLDL in placebo-treated animals to LDL in the estrogen group for both Balb/c (Fig 7A⇓ and 7B⇓) and MRL/lpr mice (Fig 7C⇓ and 7D⇓). These results demonstrate an estrogen-mediated shift of triglycerides and an increase, or redistribution, of cholesterol onto LDL particles. However, in contrast to the effects on LDL cholesterol, the shifts in triglycerides toward the LDL fraction appeared similar in both MRL/lpr and Balb/c mice. Therefore, MRL/lpr autoimmune mice exhibit a significant increase in LDL cholesterol in response to estrogen, and yet differences with Balb/c mice were not apparent when evaluating the redistribution of triglycerides to the LDL fraction.

Figure 7.
Figure 7.

Graphs showing triglyceride distribution from estriol-treated Balb/c or MRL/lpr mice. Balb/c (A, B) or MRL/lpr (C, D) were implanted with placebo (A, C) or estriol (B, D) pellets resulting in doses of 2.2 mg/kg per day of estriol. After 3 weeks mice were killed, and sera were pooled within each group and resolved by FPLC. Triglycerides were measured across the fractions. The VLDL, LDL, and HDL cholesterol peaks corresponded to fractions 5 through 10, 17 through 27, and 29 through 40, respectively. Shown is a representative experiment of three.

Discussion

Although both epidemiological and animal studies have provided convincing data regarding the beneficial effects of estrogen replacement therapy on cardiovascular disease,1 2 3 estrogen has also, in some dyslipidemias, been reported to result in an unfavorable shift in the lipoprotein profile, including increases in serum triglycerides.5 27 Estrogen treatment in the hyperlipidemic Zucker diabetic rat, for example, was associated with hypertriglyceridemia and an increase in LDL cholesterol, resulting in an increase in the LDL-to-HDL ratio.25 An increase in triglycerides associated with pancreatitis has also been observed in hypertriglyceridemic women on estrogen.27 Therefore, in both human and animal models, underlying pathologic processes may be involved in the lipoprotein response to exogenous estrogen.

In the present study, estrogen treatment of autoimmune MRL/lpr female mice resulted in a significant shift in cholesterol from HDL to LDL particles. While the effect was also apparent in MRL/++ and Balb/c mice, the extent of LDL cholesterol increase was modest. This increase in LDL cholesterol, which required pharmacologic doses of estrogen agonists, was both reversible and inhibited by the estrogen antagonist tamoxifen. Furthermore, this increase was observed with several different estrogen agonists and was apparent with both oral and parenteral formulations, suggesting that the effects of LDL cholesterol were independent of the method of administration. Finally, the redistribution of cholesterol from HDL to LDL was also associated with a shift in triglyceride from VLDL to LDL in estrogen-treated mice.

While the kinetics and dose response to estrogen agonists have been described in the present study, the mechanisms involved for this redistribution remain unclear. The increase in LDL cholesterol could be due to an increase in cholesterol content of the LDL fraction or an increased synthesis of apoB-containing particles or reflect changes in LDL catabolism. The observation that relatively similar amounts of apoE were detected within the LDL fraction between the estrogen- and placebo-treated groups in Fig 5⇑, despite a significant increase in LDL cholesterol, suggests the possibility that these LDL particles may in the estrogen group have less apoE, which could impact on LDL clearance. Whether estrogen treatment results in the generation of LDL particles with lower affinity for the LDL receptor, as suggested in human studies,26 remains to be determined.

Murine transgenics permit the simulation of human dyslipidemias in small-animal models. Development of apoE and LDL-receptor knockouts, as well as cholesteryl ester transfer protein and apolipoprotein B-100, E, and A-I transgenics, has resulted in mouse strains in which the LDL/VLDL fraction becomes a major cholesterol-carrying component of the serum.39 40 41 42 43 44 However, in contrast to the LDL-receptor or apoE homozygote or heterozygote knockouts, the shift in cholesterol observed in the estrogen-treated MRL/lpr mice was limited to the LDL fraction. There was no significant increase in VLDL-associated cholesterol in any of the mouse studies evaluated. This finding would suggest, then, a different mechanism for the estrogen-mediated shift in cholesterol distribution. Furthermore, the lack of increase in VLDL cholesterol would indicate that the estrogenic effects are not mediated by a reduction in lipoprotein lipase or hepatic lipase.

Increased triglycerides and VLDL/LDL content have been reported in a variety of animal models in which lipoprotein lipase has been inhibited by acute or chronic exposure to inflammatory mediators elicited by parasitic or bacterial infections.45 46 The well-documented hyperlipidemia associated with endotoxemia is characterized by increased triglycerides, VLDL, and LDL cholesterol, reduction in HDL cholesterol, and decreased lipoprotein lipase and hepatic lipase activity.46 Select aspects of these dyslipidemias have been reproduced after interleukin-1 injection.45

Although the relationship between the shift in cholesterol distribution in the autoimmune mice exposed to chronic estrogen treatment and inflammation remains unclear, comparative studies on the lipoprotein profile of both MRL/lpr and MRL/++ mice fed atherogenic and nonatherogenic diets have revealed interesting differences. MRL/lpr mice fed an atherogenic diet had lower levels of apoB-containing lipoproteins than the MRL/++ but a higher incidence of myocardial infarction.37 These and other results suggest that autoimmune disease may have significant effects on lipoprotein metabolism.

While the increase in LDL cholesterol observed in the MRL/lpr model required pharmacologic doses of estrogen, the ability to block these effects with tamoxifen suggested the involvement of an estrogen receptor in influencing the relative distribution of cholesterol between HDL and LDL particles. The relationship between autoimmune disease and increased cardiovascular events has been suggested and presumably reflects inflammatory events occurring within the vascular wall, the contribution of inflammatory mediators, and the side-effect profile of current therapies designed to suppress the autoimmune response. Although mice transport serum cholesterol primarily on HDL particles, the well-characterized models of autoimmunity in the murine system as well as the combination of autoimmune models on the appropriate transgenic or knockout background will contribute to our understanding of the linkages between autoimmunity and increased cardiovascular disease. In summary, the estrogen-treated MRL/lpr mouse may provide a small-animal model in which the use of both standard and novel therapeutic entities designed to impact on autoimmune and inflammatory processes can be evaluated for their effects on lipoprotein risk factors associated with atherosclerosis.

Acknowledgments

The authors wish to thank Dr Chandrasekhar for his critical review of our manuscript.

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  • Estrogen-Induced Alterations in Lipoprotein Metabolism in Autoimmune MRL/lpr Mice
    Steven H. Zuckerman and Nancy Bryan-Poole
    Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1556-1562, originally published October 1, 1995
    https://doi.org/10.1161/01.ATV.15.10.1556
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