1995 — 1997 |
Redmond, Eileen M |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Altered Vasoregulation in Portal Hypertension |
0.952 |
1999 — 2008 |
Redmond, Eileen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Alcohol Regulation of Smooth Muscle Migration and Growth @ University of Rochester
DESCRIPTION (Adapted from Applicant's Abstract): Epidemiological studies demonstrate a significant protective effect of moderate alcohol consumption or the incidence of cardiovascular disorders such as stroke, hypertension and coronary artery disease (CAD) which account for the majority of deaths in the Western world. In addition, in vivo animal studies demonstrate an inhibitory effect of ethanol on neointimal formation following balloon injury. Mechanical force-induced arterial smooth muscle cell (SMC) proliferation and migration are two distinct processes that play an important role in neointimal formation during the pathogenesis of hypertension, atherosclerosis and the arterial response to injury. Several studies have provided compelling evidence for a role of mitogen activated protein kinases (MAPKs) and urokinase plasminogen activators (uPA), plasminogen activator inhibitor (PAI-1), and matrix metalloproteinases (MMP) in regulating SMC growth and migration, respectively. Preliminary in vitro data demonstrate that increases in pulse pressure due to increases in pulsatile flow induces SMC proliferation, migration and MAPK signaling in the absence of endothelial cells. Furthermore ethanol, at physiological concentrations, inhibits pressure- and serum-induced increases in SMC migration, an effect that is mimicked by inhibiting SMC MAPK signaling, uPA and MMP expression. In addition, ethanol inhibits serum-stimulated MAPK signaling and growth of SMC, an effect that is also mimicked using a specific MAPK inhibitor. The central hypothesis is that ethanol at physiological concentrations, exerts its protective effect on cardiovascular disease, in part, by inhibiting pressure-induced increases in SMC proliferation and migration by decreasing MAPK signaling in these cells. This initial independent research project proposes to define the effects of ethanol on pulse pressure induced changes in SMC signaling, growth and migration. Utilizing a novel perfused transcapillary culture system, whereby endothelial and vascular smooth muscle cells can be chronically exposed to physiological shear stress and pulse pressures (pulsatile flow), the investigators will define the dose and temporal effects of ethanol on (i) pulse pressure induced increases in SMC proliferation and migration, (ii) pulse pressure induced changes in SMC MAPK, uPA, MMP, PAI-1 and TIMP signaling and (iii) the role of MAPK signaling in modulating pulse pressure-induced changes in uPA, MMP, TIMP and PAI-1 expression and subsequent changes in SMC migration and proliferation. Because the mortality from the complications of cardiovascular disease is so high, deciphering the mechanism whereby a substance can protect against it is clearly of major clinical importance and significance. Accordingly, it is critical to define the protective role of ethanol in ameliorating mechanical force-induced SMC proliferation and migration, processes which are hallmarks of neointimal formation and which are integral to the development of cardiovascular disease.
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1 |
2001 |
Redmond, Eileen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hemodynamic Regulation of Vascular Smooth Muscle Cell @ University of Rochester
Endothelial cells covering the inner surface of blood vessels are continuously exposed to mechanical forces associated with blood flow, which can be resolved into two components; shear stress, a tangential frictional force which acts at the endothelial cell surface, and cyclic strain, acting perpendicular to the vascular wall. Blood flow is an important determinant of vascular remodeling in endothelial intact and denuded vessels with reduce flow predisposing arteries to intimal thickening and atherosclerosis. Fluid shear stress and cyclic strain modulate endothelial function by stimulating the secretion of several factors from endothelial cells including nitric oxide (NO), prostacyclin (PGI2), transforming growth factor (TGFbeta), basic fibroblast growth factor (bGFG), endothelin, and platelet-derived growth (PDGF) that can modulate the underlying vascular smooth muscle cell growth and function. The central hypothesis of this proposal is that sustained increased ion flow modulate the growth of the underlying smooth muscle by differentially decreasing the release of mitogenic and increasing the release of anti- mitogenic substances from endothelial cells. This First Award application proposes to define the acute and chronic effects of flow on endothelial cell function and the subsequent consequences on the growth of the underlying smooth muscle. Utilizing our novel perfused transcapillary co-culture system, whereby endothelial and vascular smooth muscle cells can be simultaneously chronically exposed to physiological shear stress and cyclic strain (pulsatile flow), we will define the acute and chronic effects of flow on: (i) endothelial release of anti-mitogenic substances (NO, PGI2, and TGFbeta) and mitogenic substances (PDGF, bFGF and endothelin) in co- cultured cells (ii) endothelial control of mitogen-activated protein kinase signaling (MAPK's and p34/cdc2) and growth in the underlying vascular smooth muscle: the role of NO, PGI2 and TGFbeta. (iii) mitogen activated protein kinase signaling (MAPK's and p34/cdc2_ and growth in vascular smooth muscle cells in the absence of endothelial cells; the role of TGFbeta, PDGF, bFGF and MMP,s. It is critical to define the role of mechanical force on endothelial control of smooth muscle cell growth because the vascular endothelium is though to play a pivotal role in regulating smooth muscle cell growth in vivo and because flow has significant effect on several aspects of endothelial function. These experiments should provide valuable information central to our understanding of the important role hemodynamic forces play in vascular biology,a nd thus further our knowledge of its role in the etiology of cardiovascular disease.
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1 |
2012 — 2013 |
Redmond, Eileen M |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Role of Nogo-B in Mediating the Vascular Effects of Alcohol @ University of Rochester
DESCRIPTION (provided by applicant): Moderate consumption of alcohol (ethanol) is a negative risk factor for atherosclerosis and its clinical sequelae myocardial infarction, ischemic stroke and peripheral vascular disease. Little is known about the precise cell signaling and molecular mechanisms whereby ethanol may elicit its putative cardioprotective effects. We have previously reported that while EtOH stimulates the growth and migration of endothelial cels (EC), it inhibits vascular smooth muscle cell (SMC) growth and migration. Given the key role of both EC and SMC in the pathophysiology of atherosclerosis, the opposing effects of EtOH on these vascular cells might be expected to be synergistically cardioprotective and thus are of considerable clinical interest. Moreover, our preliminary data show that daily moderate alcohol feeding markedly inhibits intima-media thickening following carotid ligation injury in the mouse. EC and SMC express Notch receptors and several groups, including ours, have described a critical role for Notch signaling in the regulation of adult EC and SMC differentiation, proliferation and apoptosis. The expression of several components of the Notch pathway, including receptors and downstream target genes hes and hrt, are altered after experimentally induced vascular injury. Our data also demonstrate a differential effect of EtOH on Notch signaling in EC and SMC, - stimulatory and inhibitory, respectively, and further, implicate this pathway in mediating both EtOH's promotion of EC proliferation and it's attenuation of SMC proliferation. The transmembrane protein Nogo-B, expressed by both EC and SMC and in intact vessels, has recently been identified as a regulator of vascular remodeling, limiting the progression of vascular lesions after injury. Of interest, Nogo-B reportedly has opposing effects on vascular cells, promoting the migration of EC, but inhibiting the migration of SMC, possibly reflecting differences in receptor expression between the two cell types. Our preliminary data show that EtOH modulates Nogo-B expression in vascular cells. Despite a role for both Notch and Nogo in vascular remodeling regulation, and a differential effect of each in EC and SMC with respect to phenotype regulation, no studies to date have investigated an interaction of Nogo and Notch, much less as targets for alcohol. Our central hypothesis is that ethanol stimulates EC, and inhibits SMC growth and thus inhibits vascular remodeling in a Notch-dependent manner, mediated via Nogo-B. We will test this hypothesis using cultured human coronary artery EC and SMC in vitro in conjunction with in vivo studies utilizing the carotid ligation 'flow-restriction' model of vascular injury and remodeling in the mouse. Since changes in EC and SMC growth plays a prominent role in the pathogenesis of vascular disease, modulation of these processes by ethanol in a Nogo-B-dependent fashion represents a novel and potentially important mechanism underlying ethanol's cardioprotective effect. Because the mortality from cardiovascular disease is so high, deciphering a mechanism whereby a substance can protect against it is clearly of major clinical importance and significance. ! PUBLIC HEALTH RELEVANCE: Moderate alcohol consumption protects against cardiovascular disease. These experiments will provide exciting new mechanistic information central to our understanding of how alcohol mediates its differential effects on endothelial and smooth muscle cell growth, processes that are integral to the development of cardiovascular disease. Deciphering the cellular and molecular mechanisms mediating alcohol's cardiovascular protective effects should enable the design of novel therapies for cardiovascular disease.
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1 |
2015 — 2016 |
Redmond, Eileen M |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Alcohol Regulation of Resident Vascular Stem Cells. @ University of Rochester
? DESCRIPTION (provided by applicant): Vascular smooth muscle cells (vSMC) play a key role in the pathophysiology of cardiovascular disease (CVD). Emerging evidence suggests that stem cells present within the vessel wall differentiate to vSMC and are the active contributors to the remodeling and repair of the artery wall. This information highlights a new cell target to investigate for agents known to affect CVD, as well as a novel potential therapeutic target for treatment of vascular disease. While alcohol (EtOH) consumption is a well-established factor affecting the incidence and severity of CVD, its effects on the regenerative capacity of resident vascular stem cells have yet to be ascertained. A stem cell population implicated in vascular disease progression includes Sca1+ adventitial progenitor cells (APC) that reside at the medial adventitial boundary. APC proliferate and differentiate into vSMC that invade the intima in vascular injury models. Several factors have been described as regulators of stem cell self-renewal, differentiation and growth, most notably the morphogen sonic hedgehog (Shh). We have shown that a-actin negative, Hh-positive cells that co- localize with the APC population are located at the medial-adventitial boundary of normal vessels and later appear within the a-actin positive medial and intimal layer following injury. Hedgehog signaling is triggered by binding of the secreted Shh ligand with the transmembrane receptor Patched (Ptch) and is subsequently mediated by transcriptional effectors belonging to the Gli family. Components of the Hedgehog pathway are induced after vascular injury in vivo and a Hedgehog - Notch signaling axis controls vSMC growth and phenotype in vitro. Crucially, we have recently shown that local inhibition of hedgehog signaling in situ within the vessel wall attenuates intimal-medial thickening following injury. Our preliminary data now indicate that alcohol regulates the expression of hedgehog signaling components in vSMC, and that Shh controls stem cell transition to vSMC in vitro. Therefore, our overall hypothesis is that alcohol interferes with the renewal and/or differentiatio of resident vascular stem cells, and thus affects vessel remodeling and CVD, by affecting hedgehog signaling. We will test the validity of this hypothesis in vitro (APC) and in vivo (caroti ligation mouse model of atherosclerosis) and investigate the mechanism(s) whereby alcohol may modulate Hedgehog signaling, focusing on Ptch1 receptor-Caveolin-1 co-localization in lipid rafts and degradation by E3 ubiquitin ligases. Deciphering the mechanisms whereby alcohol affects cardiovascular disease is of major clinical importance and significance.
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1 |
2017 — 2021 |
Redmond, Eileen M |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vascular Protective Effects of Alcohol - Role of Notch @ University of Rochester
Abstract Moderate consumption of alcohol (EtOH) is a negative risk factor for cardiovascular disease but the precise mechanisms involved have not been elucidated. Pivotal to the initiation of vessel disease is endothelial cell (EC) dysfunction or loss. Subsequently, the growth and migration of vascular smooth muscle cells (SMC) are key processes in atherosclerotic plaque development, contributing to intima-medial thickening and vessel stenosis. Given the key role of both EC and SMC in the pathophysiology of atherosclerosis, effects of EtOH on these vascular cells are, thus, of considerable clinical interest. In this context Notch signaling has emerged as a novel potential target for alcohol. Repression of Notch signaling in arterial EC unlocks pro-inflammatory and pro-atherogenic signals that contribute to the initiation of atherosclerosis. Moreover, Notch signaling drives the differentiation of adult SMC from a contractile to a proliferative phenotype. Studies in animal models demonstrate that Notch signaling is stimulated following experimentally induced vascular injury, and point to a preferential role for SMC Notch 1 in mediating neointimal formation. We have shown that alcohol restrains SMC proliferation in vitro by inhibiting Notch signaling. In apparent contrast, alcohol stimulates Notch signaling and angiogenic activity in EC, while inhibiting monocyte chemoattractant protein-1 expression. These data highlight a differential effect of alcohol on Notch signaling in vascular EC and SMC - stimulatory and inhibitory, respectively, and further, implicate the Notch pathway in mediating both alcohols maintenance of an anti- atherogenic EC phenotype and it's attenuation of SMC proliferation, actions that might be considered synergistically atheroprotective. Indeed, moderate alcohol consumption ameliorates remodeling and plaque formation in injured mouse arteries. Recently, in SMC, we demonstrated a novel inhibitory effect of alcohol specifically on the ?-secretase cleavage activity that is critical for Notch signaling. Our preliminary data now indicate that EtOH enhances ?-secretase activity in EC. Therefore, the central hypothesis of our proposal is that moderate alcohol consumption protects against atherogenesis by differential yet synergistic effects on Notch signaling at the level of ?-secretase, in vascular smooth muscle and endothelial cells. To test our hypothesis, and delineate the mechanisms involved, we will use a novel in vitro `mock artery' stented and seeded with SMC cells under cyclic strain conditions, as well as endothelial cells exposed to physiologic and pathologic shear stresses in artificial capillaries, in conjunction with in vivo studies utilizing transgenic mice and a `flow-restriction' model of atherosclerosis. Deciphering the mechanisms whereby alcohol may protect against cardiovascular disease is of major clinical significance and will uncover new therapy targets for this common cause of morbidity and mortality.
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