- Email: [email protected]
Gender Differences at the Cellular Level
Journal of Surgical Research 180, 45–46 (2013) doi:10.1016/j.jss.2011.11.1023
COMMENTARY Gender Differences at the Cellular Level Originally submitted November 17, 2011; accepted for publication November 22, 2011
In a paper recently published in the Journal of Surgical Research, Drs. Hogg et al. from the Kibbe laboratory provide a report describing the putative interaction between nitric oxide (NO) therapy and estrogen receptors in vascular smooth muscle cells (VSMCs) isolated and cultured from male and female rodents [1]. Current literature continues to show both systems based and cellular differences due to gender [2], and the clinical challenge to translate these differences into intelligent treatment strategies makes this work very relevant. We applaud the authors for their work in moving this line of investigation forward by utilizing VSMCs from a variety of origins, including knockout murine cells to define estrogen receptors’ impact on proliferation. It has been established that estrogen receptors exist in male and female VSMC, and a role has been identified for estrogen-induced vasoprotection in models of vascular injury [3, 4]. Kibbe et al. previously demonstrated that VSMC proliferation and the ability of NO to inhibit neointimal hyperplasia is dependent on sex and hormone status [5]. To further delineate the process by which NO inhibition occurs, Hogg and coauthors have queried the role of estrogen receptor (ER) in mediating proliferation between sexes by determining whether NO mediates its antiproliferative effects on VSMC through ER-mediated signaling. The hypothesis for this work was that estrogen receptors mediate proliferation and antiproliferative effects of NO in female but not in male VSMC. The results did not support the female gender only portion of the hypothesis, but it did generate a number of interesting findings that may guide future work. The authors first concluded there was no difference in estrogen receptor expression in aortic VSMCs between the sexes in rats. The inhibition of ERa or ERb had no effect on proliferation of VSMC in the absence of NO in either sex. Highlights for VSMCs from female rodents include: (1) that blocking ERab in rat VSMC mitigated NO-mediated inhibition of mitogenesis in females but not males, (2) that combined inhibition of ERa and ERb abrogated the antiproliferative effects of NO in all female cell types, and (3) NO is most effective in ERaKO compared with wild type and ERbKO, suggesting NO may mediate its role through the ERb receptor. These findings support a role for ERs in mediating NO antiproliferative effects on VSMC in females. For male rodent VSMCs: (1) there were no differences in the antiproliferative effects of NO in ERa, ERb, and wild type VSMC, but the ERaKO and ERbKO VSMC proliferated at greater rates than wild type VSMC. This supports a role for ERa and ERb in regulating basal proliferation in males, but the effects of NO are not mediated through
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0022-4804/$36.00 Ó 2013 Elsevier Inc. All rights reserved.
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JOURNAL OF SURGICAL RESEARCH: VOL. 180, NO. 1, MARCH 2013
either receptor. In conclusion, the authors determined that ERa and ERb may serve to repress proliferation in males, whereas only ERb does so in females. Complicating these findings are contrary reports in the literature on the role of specific estrogen receptors in disease. For example, whether NO is mediated by ERa or alone is not clear in female murine models [6]. This most recent inquiry into the role of ERs confirms previous notions of NO antiproliferative activity but also it nicely demonstrates the challenge of targeted estrogen therapies in identifying exact mechanistic roles due to interdependent systems and redundant signaling pathways [7]. Intelligent strategies to develop gender- and hormone status-specific therapies, such as those employed by the Kibbe laboratory, are to be applauded, but identifying the right patient for the right therapy at the right time remains an elusive goal [8]. Robert Allen, M.D. Luke Packard Brewster, M.D., Ph.D., M.A.1 Department of Surgery Emory University Hospital 676 North Parkwood Road Decatur, GA
REFERENCES 1. Hogg ME, Vavra AK, Banerjee MN, et al. The role of estrogen receptor a and b in regulating vascular smooth muscle cell proliferation is based on sex. J Surg Res 2012;173:e1. 2. Collier SR, Frechette V, Sandberg K, et al. Sex differences in resting hemodynamics and arterial stiffness following 4 weeks of resistance versus aerobic exercise training in individuals with pre-hypertension to stage 1 hypertension. Biol Sex Differ 2011;2:9. 3. Bakir S, Mori T, Durand J, et al. Estrogen-induced vasoprotection is estrogen receptor dependent: Evidence from the balloon-injured rat carotid artery model. Circulation 2000; 101:2342. 4. Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 1994;89:1943. 5. Hogg ME, Varu VN, Vavra AK, et al. Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status. Free Radic Biol Med 2011;50:1065. 6. Khandelwal AR, Hebert VY, Dugas TR. Essential role of ER-a-dependent NO production in resveratrol-mediated inhibition of restenosis. Am J Physiol Heart Circ Physiol 2010; 299:H1451. 7. Xing D, Nozell S, Chen YF, et al. Estrogen and mechanisms of vascular protection. Arterioscler Thromb Vasc Biol 2009;29:289. 8. Brewster LP, Brey EM, Greisler HP. Cardiovascular gene delivery: The good road is awaiting. Adv Drug Deliv Rev 2006;58:604.
1
To whom correspondence and reprint requests should be addressed at Department of Surgery, Emory University Hospital, 676 North Parkwood Road, Decatur, GA 30030. E-mail: [email protected].
COMMENTARY Gender Differences at the Cellular Level Originally submitted November 17, 2011; accepted for publication November 22, 2011
In a paper recently published in the Journal of Surgical Research, Drs. Hogg et al. from the Kibbe laboratory provide a report describing the putative interaction between nitric oxide (NO) therapy and estrogen receptors in vascular smooth muscle cells (VSMCs) isolated and cultured from male and female rodents [1]. Current literature continues to show both systems based and cellular differences due to gender [2], and the clinical challenge to translate these differences into intelligent treatment strategies makes this work very relevant. We applaud the authors for their work in moving this line of investigation forward by utilizing VSMCs from a variety of origins, including knockout murine cells to define estrogen receptors’ impact on proliferation. It has been established that estrogen receptors exist in male and female VSMC, and a role has been identified for estrogen-induced vasoprotection in models of vascular injury [3, 4]. Kibbe et al. previously demonstrated that VSMC proliferation and the ability of NO to inhibit neointimal hyperplasia is dependent on sex and hormone status [5]. To further delineate the process by which NO inhibition occurs, Hogg and coauthors have queried the role of estrogen receptor (ER) in mediating proliferation between sexes by determining whether NO mediates its antiproliferative effects on VSMC through ER-mediated signaling. The hypothesis for this work was that estrogen receptors mediate proliferation and antiproliferative effects of NO in female but not in male VSMC. The results did not support the female gender only portion of the hypothesis, but it did generate a number of interesting findings that may guide future work. The authors first concluded there was no difference in estrogen receptor expression in aortic VSMCs between the sexes in rats. The inhibition of ERa or ERb had no effect on proliferation of VSMC in the absence of NO in either sex. Highlights for VSMCs from female rodents include: (1) that blocking ERab in rat VSMC mitigated NO-mediated inhibition of mitogenesis in females but not males, (2) that combined inhibition of ERa and ERb abrogated the antiproliferative effects of NO in all female cell types, and (3) NO is most effective in ERaKO compared with wild type and ERbKO, suggesting NO may mediate its role through the ERb receptor. These findings support a role for ERs in mediating NO antiproliferative effects on VSMC in females. For male rodent VSMCs: (1) there were no differences in the antiproliferative effects of NO in ERa, ERb, and wild type VSMC, but the ERaKO and ERbKO VSMC proliferated at greater rates than wild type VSMC. This supports a role for ERa and ERb in regulating basal proliferation in males, but the effects of NO are not mediated through
45
0022-4804/$36.00 Ó 2013 Elsevier Inc. All rights reserved.
46
JOURNAL OF SURGICAL RESEARCH: VOL. 180, NO. 1, MARCH 2013
either receptor. In conclusion, the authors determined that ERa and ERb may serve to repress proliferation in males, whereas only ERb does so in females. Complicating these findings are contrary reports in the literature on the role of specific estrogen receptors in disease. For example, whether NO is mediated by ERa or alone is not clear in female murine models [6]. This most recent inquiry into the role of ERs confirms previous notions of NO antiproliferative activity but also it nicely demonstrates the challenge of targeted estrogen therapies in identifying exact mechanistic roles due to interdependent systems and redundant signaling pathways [7]. Intelligent strategies to develop gender- and hormone status-specific therapies, such as those employed by the Kibbe laboratory, are to be applauded, but identifying the right patient for the right therapy at the right time remains an elusive goal [8]. Robert Allen, M.D. Luke Packard Brewster, M.D., Ph.D., M.A.1 Department of Surgery Emory University Hospital 676 North Parkwood Road Decatur, GA
REFERENCES 1. Hogg ME, Vavra AK, Banerjee MN, et al. The role of estrogen receptor a and b in regulating vascular smooth muscle cell proliferation is based on sex. J Surg Res 2012;173:e1. 2. Collier SR, Frechette V, Sandberg K, et al. Sex differences in resting hemodynamics and arterial stiffness following 4 weeks of resistance versus aerobic exercise training in individuals with pre-hypertension to stage 1 hypertension. Biol Sex Differ 2011;2:9. 3. Bakir S, Mori T, Durand J, et al. Estrogen-induced vasoprotection is estrogen receptor dependent: Evidence from the balloon-injured rat carotid artery model. Circulation 2000; 101:2342. 4. Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 1994;89:1943. 5. Hogg ME, Varu VN, Vavra AK, et al. Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status. Free Radic Biol Med 2011;50:1065. 6. Khandelwal AR, Hebert VY, Dugas TR. Essential role of ER-a-dependent NO production in resveratrol-mediated inhibition of restenosis. Am J Physiol Heart Circ Physiol 2010; 299:H1451. 7. Xing D, Nozell S, Chen YF, et al. Estrogen and mechanisms of vascular protection. Arterioscler Thromb Vasc Biol 2009;29:289. 8. Brewster LP, Brey EM, Greisler HP. Cardiovascular gene delivery: The good road is awaiting. Adv Drug Deliv Rev 2006;58:604.
1
To whom correspondence and reprint requests should be addressed at Department of Surgery, Emory University Hospital, 676 North Parkwood Road, Decatur, GA 30030. E-mail: [email protected].