Rapid Estrogen Receptor Signaling Is Essential for the Protective Effects of Estrogen Against Vascular Injury

Abstract

Background Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which when bound to estrogen can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a “rapid” non-nuclear signaling cascade. However, the biologic significance of this rapid signaling pathway has been unclear. Methods and Results Here, we develop a novel transgenic mouse in which rapid signaling is blocked by over-expression of a peptide that prevents ERs from interacting with the scaffold protein, striatin (the Disrupting Peptide Mouse, DPM). Microarray analysis of ex vivo-treated mouse aortas demonstrates that rapid ER signaling plays an important role in estrogen-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the DPM mouse following carotid artery wire injury. Conclusions Taken together, these results support that rapid, non-nuclear ER signaling contributes to the transcriptional regulatory functions of ER, and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents.

Sex and Menopause Differences in Response to Tadalafil: 6‐Minute Walk Distance and Time to Clinical Worsening

“…14,15 Multiple animal studies have demonstrated that estrogen decreases pulmonary arterial vasoconstriction by decreasing expression of endothelin 1 and increasing release of NO and prostaglandin. 8,[16][17][18][19][20] Neither of these studies addressed the effect of menopause on treatment response or evaluated time to clinical worsening (TCW) as a clinical end point.In the general population, many vasoreactive conditions, such as migraine headache and Raynaud's phenomenon, increase after menopause. 17 This postmenopausal increase is also demonstrated in PAH and is postulated to be due to estrogen withdrawal, as it has been demonstrated in animal models that lower estrogen and progesterone states produce increased pulmonary vasoconstriction.…”

STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

“…[6][7][8][9][10][11][12][13][14][15] In vascular smooth muscle cells (SMCs), PY-STAT5b has been identified as a transcription factor which facilitates growth and motility, and neointima formation in response to thrombin, PDGF and arterial injury. [21][22][23][24][25][71][72][73][74] Suppression of activation of PY-STAT5b signaling in the vessel wall reduced balloon injury-induced neointima formation. 73 Remarkably, that hypophysectomy in the male rat markedly impaired arterial remodeling after aortic balloon injury due to reduced vascular SMC proliferation and myointima formation, was reported in 1978, 75 and confirmed, 76 but the mechanisms remained to be elucidated.…”

“…As examples, there is an extensive literature on the effects of E2 on increasing the function of eNOS in endothelial cells, the ability of E2 to stimulate vascular smooth muscle cell proliferation, and to inhibit the trafficking of vasorelevant receptors such as BMPR2 (bone morphogenetic receptor 2) to the cell surface. 6,[21][22][23][24][25][26][27][28] However, these studies of direct effects of sex hormones on vascular cells, taken together, have been unable to explain the many disparate sex bias observations in a vascular disease such as PH in humans and different rodent species.…”

Striatin-Dependent Membrane Estrogen Receptor Signaling and Vasoprotection by Estrogens

“…7 Striatin is a member of the WD (tryptophan [W], aspartic acid [D]) repeat protein family containing a caveolin-binding domain as well as a calmodulin binding domain and serves as a molecular anchor and scaffold for assembly of proteins required for rapid estrogeninduced signaling. 8 In the study by Moens and associates in this issue of Circulation, 4 the actions of this receptor complex are defined using a novel transgenic mouse expressing a disrupting peptide consisting of the striatin-binding domain within ER␣. This peptide prevents complex formation between ER␣ and ER␤ and striatin and inhibits membrane ER signaling.…”

“…To achieve this aim, new studies to better understand both nuclear and membrane estrogen receptor (ER)-mediated signaling in target tissues such as the heart and blood vessels, immune cells, and other target tissues are in progress. In this issue of Circulation, Moens and colleagues 4 provide novel insights on the importance of membrane ER-mediated signaling pathways in blood vessels for vasoprotection and vascular gene regulation.…”