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Wake Forest, NC, United States

Lindsey S.H.,Tulane University | Liu L.,Tulane University | Chappell M.C.,Hypertension and Vascular Research Center
Steroids | Year: 2014

Our previous work showed that chronic activation of the membrane-bound estrogen receptor GPR30/GPER significantly lowers blood pressure in ovariectomized hypertensive mRen2.Lewis female rats which may, in part, reflect direct vasodilatory actions. The current study assessed the hypothesis that cyclic adenosine monophosphate (cAMP) signaling contributes to GPER-mediated vasorelaxation. In mesenteric resistance arteries from intact Lewis females, relaxation to 17-β-estradiol (E2; 47 ± 3% of phenylephrine contraction vs. vehicle 89 ± 2%, P < 0.001) or G-1 (44 ± 8%, P < 0.001) was blunted to a similar extent by denuding (P < 0.001) or the nitric oxide synthase inhibitor l-NAME (P < 0.001). In contrast, the cyclooxygenase inhibitor indomethacin did not alter vasodilation (P > 0.05). The cAMP analog Rp-cAMPS partially attenuated vasodilation (65 ± 7%, P < 0.001), while the combination of l-NAME and Rp-cAMPS exhibited additive effects to effectively abolish vasorelaxation (P > 0.05 vs. vehicle). Pretreatment of endothelium-intact vessels with the adenylyl cyclase inhibitor SQ (63 ± 6%) or the guanylyl cyclase inhibitor ODQ (62 ± 9%) both partially inhibited the response to G-1 (P < 0.01), while pretreatment with the both inhibitors completely abolished vasorelaxation (P > 0.05 vs. vehicle). In denuded vessels only SQ reduced the response (88 ± 3%, P < 0.001). Moreover, G-1 significantly increased intracellular cAMP levels in cultured mesenteric smooth muscle cells (P < 0.05). We conclude that GPER-dependent vasorelaxation apparently involves both endothelial release of nitric oxide which activates guanylyl cyclase and smooth muscle cell activation of adenylyl cyclase. Downstream production of cyclic nucleotides and stimulation of protein kinases may phosphorylate proteins to promote vascular smooth muscle cell relaxation. The ability of GPER to initiate these signaling pathways may contribute to the beneficial vascular effects of estrogen. © 2013 Elsevier Inc. All rights reserved.


Moore E.D.,Nutrition Research Center | Metheny-Barlow L.J.,Nutrition Research Center | Gallagher P.E.,Hypertension and Vascular Research Center | Robbins M.E.,Nutrition Research Center
Free Radical Biology and Medicine | Year: 2013

About 500,000 new cancer patients will develop brain metastases in 2013. The primary treatment modality for these patients is partial or whole brain irradiation which leads to a progressive, irreversible cognitive impairment. Although the exact mechanisms behind this radiation-induced brain injury are unknown, neuroinflammation in glial populations is hypothesized to play a role. Blockers of the renin-angiotensin system (RAS) prevent radiation-induced cognitive impairment and modulate radiation-induced neuroinflammation. Recent studies suggest that RAS blockers may reduce inflammation by increasing endogenous concentrations of the anti-inflammatory heptapeptide angiotensin-(1-7) [Ang-(1-7)]. Ang-(1-7) binds to the AT(1-7) receptor and inhibits MAP kinase activity to prevent inflammation. This study describes the inflammatory response to radiation in astrocytes characterized by radiation-induced increases in (i) IL-1β and IL-6 gene expression; (ii) COX-2 and GFAP immunoreactivity; (iii) activation of AP-1 and NF-κB transcription factors; and (iv) PKCα, MEK, and ERK (MAP kinase) activation. Treatment with U-0126, a MEK inhibitor, demonstrates that this radiation-induced inflammation in astrocytes is mediated through the MAP kinase pathway. Ang-(1-7) inhibits radiation-induced inflammation, increases in PKCα, and MAP kinase pathway activation (phosphorylation of MEK and ERK). Additionally Ang-(1-7) treatment leads to an increase in dual specificity phosphatase 1 (DUSP1). Furthermore, treatment with sodium vanadate (Na 3VO4), a phosphatase inhibitor, blocks Ang-(1-7) inhibition of radiation-induced inflammation and MAP kinase activation, suggesting that Ang-(1-7) alters phosphatase activity to inhibit radiation-induced inflammation. These data suggest that RAS blockers inhibit radiation-induced inflammation and prevent radiation-induced cognitive impairment not only by reducing Ang II but also by increasing Ang-(1-7) levels. © 2013 Elsevier B.V. All rights reserved.


Lindsey S.H.,Hypertension and Vascular Research Center | Chappell M.C.,Hypertension and Vascular Research Center
Gender Medicine | Year: 2011

Although female protection from cardiovascular diseases declines with the fall in circulating sex hormones experienced during menopause, clinical trials in older women fail to demonstrate beneficial effects for hormone replacement therapy. The recent discovery of GPR30, a membrane-bound estrogen receptor that is structurally and functionally unique from the steroid receptors ERα and ERβ, has unveiled additional signaling pathways by which estrogen may influence cardiovascular health. This review takes an organ-based approach to assess the expression and function of GPR30 in the cardiovascular system. We concluded that although the current literature does suggest a cardiovascular role for GPR30, additional exploration is necessary to fully elucidate the estrogenic actions mediated by this novel receptor. © 2011 Elsevier HS Journals, Inc. All rights reserved.


Wang H.,Medical Center Boulevard | Jessup J.A.,Medical Center Boulevard | Lin M.S.,Medical Center Boulevard | Chagas C.,Medical Center Boulevard | And 2 more authors.
Cardiovascular Research | Year: 2012

Aims: GPR30 is a novel oestrogen receptor expressed in various tissues, including the heart. We determined the role of GPR30 in the maintenance of left ventricular (LV) structure and diastolic function after the surgical loss of ovarian hormones in the female mRen2.Lewis rat, a model emulating the cardiac phenotype of the post-menopausal woman. Methods and results: Bilateral oophorectomy (OVX) or sham surgery was performed in study rats; the selective GPR30 agonist, G-1 (50 g/kg/day), or vehicle was given subcutaneously to OVX rats from 1315 weeks of age. Similar to the cardiac phenotype of sham rats, G-1 preserved diastolic function and structure relative to vehicle-treated OVX littermates independent of changes in blood pressure. G-1 limited the OVX-induced increase in LV filling pressure, LV mass, wall thickness, interstitial collagen deposition, atrial natriuretic factor and brain natriuretic peptide mRNA levels, and cardiac NAD(P)H oxidase 4 (NOX4) expression. In vitro studies showed that G-1 inhibited angiotensin II-induced hypertrophy in H9c2 cardiomyocytes, evidenced by reductions in cell size, protein content per cell, and atrial natriuretic factor mRNA levels. The GPR30 antagonist, G15, inhibited the protective effects of both oestradiol and G-1 on this hypertrophy. Conclusion: These data show that the GPR30 agonist G-1 mitigates the adverse effects of oestrogen loss on LV remodelling and the development of diastolic dysfunction in the study rats. This expands our knowledge of the sex-specific mechanisms underlying diastolic dysfunction and provides a potential therapeutic target for reducing the progression of this cardiovascular disease process in post-menopausal women. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.


Marshall A.C.,Hypertension and Vascular Research Center | Shaltout H.A.,Hypertension and Vascular Research Center | Shaltout H.A.,Alexandria University | Pirro N.T.,Hypertension and Vascular Research Center | And 2 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2013

Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensinconverting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min-1·ml-1; P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals. © 2013 the American Physiological Society.

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