Cardiovascular disease is responsible for nearly 17 million deaths each year worldwide, and vascular disorders account for over three-fourths of these deaths. The initiating events for many vascular diseases, including atherosclerosis, hypertension, preeclampsia, and diabetic and immune-mediated vasculopathies entail abnormalities in endothelial cell signal transduction. A unifying pathogenetic feature in all of these conditions is an early attenuation in nitric oxide (NO) production by the endothelial isoform of NO synthase (eNOS). NO serves multiple functions in the vascular wall, mediating endothelial and vascular smooth muscle cell growth, migration and apoptosis, the adhesion of platelets and leukocytes, and smooth muscle cell relaxation. In earlier studies of the mechanisms which converge to regulate eNOS, our laboratory demonstrated that the enzyme is targeted via acylation to caveolae, which are a subset of plasma membrane lipid rafts enriched in cholesterol and sphingomyelin. The OVERALL GOAL of our laboratory is to identify the molecular components, the protein-protein interactions, and the regulatory events occurring within signaling modules on the plasma membrane which dictate endothelial cell phenotype and the propensity for vascular disease. Currently there are three major areas of investigation: 1) nongenomic actions of estrogen mediated by plasma membrane-associated estrogen receptor (ER) alpha and beta. Nongenomic ER actions are critically involved in the cardiovascular protection afforded by estrogen. The molecular basis of novel G protein coupling of membrane ER and the downstream targets modifying endothelial cell phenotype are being determined. In addition, we have recently identified a cholesterol metabolite, 27-hydroxycholesterol (27HC), which is prevalent in atherosclerotic lesions and causes potent ER antagonism. A new hypothesis is that 27HC antagonism of ER underlies the failure of estrogen replacement therapy to prevent cardiovascular disease in women with established atherosclerosis. 2) signaling by scavenger receptor BI (SR-BI), the high affinity receptor for HDL. Our recent studies indicate that SR-BI serves as a cholesterol sensor on the endothelial cell plasma membrane, yielding potent changes in endothelial cell phenotype which may underlie the antiatherogenic properties of HDL. The molecular mechanisms underlying cholesterol sensing and resulting signal initiation are being pursued. 3) negative regulation of signaling by the pentraxin C-reactive protein (CRP). CRP is an acute phase reactant that is elevated under inflammatory conditions and with obesity. Chronic elevations in circulating CRP are now known to be an important risk factor for cardiovascular disease, with numerous studies indicating that they are as predictive as lipid profiles. We have recently discovered that CRP prevent eNOS activation and normal endothelial function via binding to Fc gamma RIIB, which is an inhibitory IgG receptor. These mechanisms provide novel causal linkage between inflammation and obesity and vascular disease, and their molecular underpinnings and implications are under study. An additional new area of investigation is focused on negative regulation of signaling by antiphospholipid (aPL) antibodies. The aPL syndrome is characterized by the presence of circulating aPL antibodies, thrombosis and pregnancy loss. We have recently discovered that aPL antibodies cause potent antagonism of eNOS activation which results in the disruption of multiple normal functions of endothelium. Candidate receptors and adaptor molecules necessary for aPL action are now being identified. Investigations are being performed in cell culture models and in both in vitro and in vivo reconstitution systems. Multiple gain-of-function and loss-of-function approaches are also being employed in genetically-engineered mice to reveal both mechanistic information and the role of altered endothelial cell function in the genesis of vascular diseases. Readouts in intact mice utilized in our studies include acute determinations of endothelial NO production, the chronic measurement of blood pressure by radiotelemetry, the evaluation of reendothelialization indicative of endothelial cell growth and migration in vivo, and models of arterial injury and neointima formation. In addition, strategies have been developed to interrogate changes in endothelial cell gene expression in vivo during normal development and during disease initiation. Springboarding from the insights gained in the laboratory, population-based analyses of the genetic determinants of endothelial dysfunction are also under way. With a continued focus on fundamental regulatory mechanisms in endothelial cell biology, the ultimate goal of the research program is to elucidate bases for new preventative and treatment strategies for vascular disease.
Vongpatanasin W, Thomas GD, Schwartz R, Cassis LA, Osborne-Lawrence S, Hahner L, Gibson LL, Black S, Samols D, Shaul PW, "CRP causes downregulation of vascular AT2 receptors and systolic hypertension in mice" Circulation, 115:1020-1028, 2007
Kumar P, Tall GG, Chambliss KL, Yuhanna IS, Wu Q, Mumby SM, Mineo C, Shaul PW, "Direct interactions with Galpha i and Gbeta-gamma mediate nongenomic signaling by ERalpha" Mol. Endocrinol., 21:1370-1380, 2007
Schwartz R, Osborne-Lawrence S, Hahner L, Gibson LL, Gormley AK, Vongpatanasin W, Zhu W, Word RA, Seetharam D, Black S, Samols D, Mineo C, Shaul PW, "CRP downregulates endothelial NO synthase and attenuates reendothelialization in vivo in mice" Circ. Res., 100:1452-1459, 2007
Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Liverman AB, Javitt NB, Shaul PW, Mangelsdorf DJ, "27-Hydroxycholesterol is an endogenous selective estrogen receptor modulator that inhibits the cardiovascular effects of estrogen" Nat. Med., 2007
SIGNIFICANT PUBLICATIONS
Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW, "Estrogen receptor alpha mediates nongenomic activation of eNOS by estrogen" J. Clin. Invest., 130:401-406, 1999
Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, Anderson RGW, Mendelshoh ME, Hobbs HH, Shaul PW, "High density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase" Nature Med., 7:853-857, 2001
Shaul PW, Smart EJ, Robinson LJ, German Z, Yuhanna IS, Ying Y, Anderson RGW, Michel T, "Acylation targets endothelial nitric oxide synthase to plasmalemmal caveolae" J. Biol. Chem., 271:6518-6522, 1996
Assanasen C, Mineo C, Seetharam D, Yuhanna IS, Marcel YL, Connelly MA, Williams DL, de la Llera-Moya M, Shaul PW, Silver DL, "Cholesterol binding, efflux and a PDZ-interacting domain of SR-BI mediate HDL-initiated signaling" J. Clin. Invest., 115:969-977, 2005
Mineo C, Gormley AK, Yuhanna IS, Osborne-Lawrence S, Gibson LL, Hahner L, Shohet RV, Black S, Salmon JE, Samols D, Karp DR, Thomas GD, Shaul PW, "FcRIIB mediates C-reactive protein inhibition of endothelial NO synthase" Circ. Res., 97:1124-1131, 2005
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