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Effect of Estrogen on Endothelial Function

Figure 1: Summary Figure. The hypothalamus releases GnRH (gonadotropin-releasing hormone). GnRH causes gonadotropins FSH (follicle-stimulating hormone) and LH (luteinizing hormone) to be secreted. FSH and LH bind to receptors in the female ovary ultimately causing estrogen to be produced. When estrogen is released into the bloodstream, an increase in vasodilation is seen within the vasculature. Created with BioRender.com.

Introduction

Sex hormones play a role in many physiological processes throughout the body (1). Specifically, these hormones are chemical messengers that bind to receptors and cause a variety of effects on target tissues. Estrogen is a female sex hormone that is secreted by the ovaries (2). For the purpose of this review, we will discuss the effect that estrogen has on endothelial function. The following will discuss what endothelial function and estrogen are, and how an increase in vasodilation occurs in the presence of estrogen.

Section 1: Background Physiology

What is endothelial function?

The endothelium is a thin membrane that lines the inside of the vasculature (3). It is made up of a single layer of endothelial cells (Figure 2A). This innermost layer regulates a variety of mechanisms but for the purpose of this review, we will discuss its role in controlling vascular contraction and relaxation. Endothelial cells release specific vasodilators and vasoconstrictors to control blood flow. One of the main vasodilators used to regulate vascular tone is nitric oxide (4) (Figure 2B).

Figure 2: Endothelial Function. A) The endothelium is made up of endothelial cells and is the inner layer of the vasculature. B) Nitric oxide (NO) is released by endothelial cells and causes the vasculature to dilate. In A, we see the vasculature at a resting diameter. In B, NO is released from the endothelial cells and vasodilation occurs. Created with BioRender.com.

How is nitric oxide produced?

Nitric oxide that is produced in the endothelium is called endothelial-derived nitric oxide and is produced by endothelial nitric oxide synthase (eNOS) (5). When activated by calcium, a series of steps form superoxide. When the amino acid l-arginine and tetrahydrobiopterin (BH4) are present, eNOS transfers the electrons from superoxide onto a part of arginine to form nitric oxide. Nitric oxide then travels out of the endothelium to the smooth muscle, causing the blood vessel to increase its diameter. High levels of intracellular calcium and phosphorylation of different parts of this enzyme increase eNOS activity.

Figure 3: Production of Nitric Oxide (NO) Through Endothelial Nitric Oxide Synthase (eNOS). In the presence of l-arginine and BH4, eNOS transfers electrons from superoxide onto arginine and NO is formed. This happens within the endothelium. NO then travels out of the endothelium to the smooth muscle. Created with BioRender.com.

What is Estrogen?

Within the brain is the hypothalamus. The hypothalamus signals for many hormones to be released. One hormone the hypothalamus releases is gonadotropin-releasing hormone (GnRH) (6). GnRH causes the anterior pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). When LH is present, it binds to receptors in thecal cells which are located within the ovary. The binding of LH causes a series of steps, eventually leading to the presence of androstenedione. When androstenedione is present, it travels through the basement membrane into the granulosa cell which is located within the thecal cell. When FSH is present, it binds to receptors in the granulosa cell. The binding of FSH causes a series of steps, converting androstenedione into estrogen. Estrogen then travels through the basement membrane and into the bloodstream (2).

Across the female lifespan, we see changes in the amount of estrogen that is produced (7). After puberty, we see high amounts of estrogen. At the end of a female’s reproductive stage, we see the amount of estrogen present decrease gradually, eventually reaching an extremely low level of estrogen that remains constant. This is due to a ceasing of the menstrual cycle, which is known as menopause.

There are three major forms of estrogen (7). Estradiol is the primary form of estrogen made during the reproductive years of a female’s life. Estriol is the primary form of estrogen during a female’s pregnancy. Estrone is the primary form of estrogen that is present in the body after menopause.

Figure 4: Estrogen Production in the Ovary. In the presence of luteinizing hormone (2) androstenedione is produced within the thecal cells. Androstenedione goes through the basement membrane into the granulosa cells. In the presence of follicle-stimulating hormone (FSH) androstenedione is converted into estrogen. Estrogen then goes through the basement membrane and into the bloodstream. Created with BioRender.com.

Section 2: How Does Estrogen Affect Endothelial Function?

Estrogen affects endothelial function by the effect it has on eNOS. There are three proposed mechanisms by which estrogen activates eNOS. First, when estradiol binds with estrogen receptor α (ERα), a series of steps occurs and causes phosphorylation at Serine-1177. Second, when estrogen and the mitogen-activated protein kinase (MAPK) pathway are present, eNOS activation increases. Third, catechol estradiols increase AMP-activated protein kinase (AMPK) which causes Hsp90 to bind with eNOS.

As mentioned previously, phosphorylation of different parts of the enzyme eNOS increases eNOS activity. When estradiol binds with ERα, Src kinase (non-receptor tyrosine kinase protein) and PI3K (phosphatidylinositol-3-OH kinase) are activated, eventually leading to the activation of Akt (a serine/threonine-protein kinase) (8). When Akt is activated, phosphorylation at Serine-1177 (eNOS phosphorylation site) occurs. This causes eNOS to become more sensitive to calcium, in turn causing more nitric oxide to be produced. In other words, increased eNOS sensitivity means eNOS can be active at much lower amounts of calcium concentrations (8). This process is known as ERα-mediated eNOS activation.

In order for ERα-mediated eNOS activation to work properly, the MAPK pathway must not be hindered. The exact pathway for this observation is unclear, but research by Chen et al. (9) found that when MAPK is inhibited, the effect of estrogen is diminished, suggesting that MAPK does play a role in ERα-mediated eNOS activation.

An additional pathway that regulates the effect estrogen has on eNOS is the activation of AMPK through heat shock protein 90 (Hsp90) binding (10). The following is the proposed pathway. When estradiol is converted into hydroxyestradiols (i.e. catechol estradiols), AMPK is activated (11). When AMPK is activated, the amount of Hsp90 bound with eNOS increases. The binding of Hsp90 to eNOS enhances the activation of eNOS, therefore leading to an increase in nitric oxide production.

Figure 5: The Effect of Estrogen on eNOS. There are three proposed mechanisms by which estrogen activates eNOS. The pathway on the left shows when estradiol is converted into catechol estradiols, AMPK is activated. This causes Hsp90 to bind to eNOS. The pathway in the middle shows when the MAPK pathway is activated, eNOS is activated. The pathway on the right shows that when estradiol binds with ERα, Src and PI3K are activated, eventually leading to the activation of Akt. Then, phosphorylation at Ser-1177 occurs. Created with BioRender.com.

Section 3: What Is Unknown and What’s Next?

We know that estrogen causes an increase in nitric oxide and therefore increases vasodilation. When estrogen is low, like during menopause, we see a decrease in vasodilatory capacity. No conclusion has been made as to whether females will continue normal vasodilatory function through exogenous means (such as hormone therapy) once reaching menopause, or whether the loss of the menstrual cycle causes some irreversible damage to this function. In low states of estrogen, the risk of cardiovascular disease increases. Determining how to mitigate the effects of low estrogen is needed.

Conclusion

Estrogen is a female sex hormone that is secreted by the ovaries and fluctuates throughout the female lifespan. Research shows that estrogen affects endothelial function by the effect it has on eNOS. In low states of estrogen, the risk of cardiovascular disease increases. More research is needed to determine how to mitigate the effects of low estrogen to prevent cardiovascular disease.

References

  1. Campbell M, Jialal I. Physiology, Endocrine Hormones. [Updated 2021 Oct 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
  2. Mihm M, Gangooly S, Muttukrishna S. The normal menstrual cycle in women. Anim Reprod Sci. 2011;124(3-4):229-236.
  3. Félétou M. The Endothelium: Part 1: Multiple Functions of the Endothelial Cells—Focus on Endothelium-Derived Vasoactive Mediators. San Rafael (CA): Morgan & Claypool Life Sciences; 2011. Author Biography.
  4. Tousoulis D, Kampoli AM, Tentolouris C, Papageorgiou N, Stefanadis C. The role of nitric oxide on endothelial function. Curr Vasc Pharmacol. 2012 Jan;10(1):4-18. doi: 10.2174/157016112798829760. PMID: 22112350.
  5. Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113(13):1708-1714.
  6. Shahid Z, Asuka E, Singh G. Physiology, Hypothalamus. [Updated 2021 May 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
  7. Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med. 2013;19(3):197-209. doi:10.1016/j.molmed.2012.12.007
  8. Haynes MP, Li L, Sinha D. Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem. 2003;278(4):2118-2123.
  9. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest. 1999;103(3):401-406.
  10. Garcia-Cardena G, Fan R, Shah V. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature. 1998;392(6678):821-824.
  11. Schulz E, Anter E, Zou MH, Keaney JF, Jr. Estradiol-mediated endothelial nitric oxide synthase association with heat shock protein 90 requires adenosine monophosphate-dependent protein kinase. Circulation. 2005;111(25):3473-3480.

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